JP2004002318A - Nitrogen-containing heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent having the activity of promoting osteoblast necessary for metabolic osteopathy including osteoporosis. <P>SOLUTION: A nitrogen-containing heterocyclic compound as the therapeutic agent is represented by the formula(1)[ wherein, X<SP>1</SP>and X<SP>2</SP>are each N or CR<SP>5</SP>, at least one of them being N; Y is N or, when X<SP>1</SP>and X<SP>2</SP>are both N, CR<SP>6</SP>; R<SP>1</SP>is NR<SB>a</SB>R<SB>b</SB>, an aryl, cycloalkyl or the like; wherein R<SB>a</SB>and R<SB>b</SB>are each H, CO, a lower alkyl or the like; E is a single bond, 1-3C alkylene, vinylene(-C=C-) or the like; and R<SP>2</SP>is an aryl, heteroaryl or the like ], being i.e. a 3,6-disubstituted 1,2,4-triazolo[4,3-b]pyridazine such as 6-azocan-1-yl-3(6-methoxypyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2004,JPO

Description

（式中の記号は以下の意味を有する。
Ｘ^１及びＸ^２：同一又は異なって、Ｎ、又はＣＲ^５、少なくとも一方はＮ、
Ｙ：Ｎ、又はＸ^１及びＸ^２が共にＮのとき、ＹはＣＲ^６であってもよい、
点線：単結合又は二重結合、
Ｒ^１：−ＮＲａＲｂ、但し、基−Ｅ−Ｒ^２がｍ位に置換基を有するフェニル又は６位に置換基を有する２−ピリジルであるとき、Ｒ^１は、置換基を有していてもよいアリール、置換基を有していてもよいシクロアルキル、置換基を有していてもよいシクロアルケニル、−Ｏ−（置換基を有していてもよいアリール）、−Ｓ−（置換基を有していてもよいアリール）、−Ｏ−Ｃ_１−２アルキレン−（置換基を有していてもよいアリール）、−Ｏ−Ｃ_１−２アルキレン−（置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環）又は−Ｏ−Ｃ_１−２アルキレン−ＯＲ’であってもよい、
Ｒａ及びＲｂ：同一又は異なって、Ｈ；ＣＯ−低級アルキル；ＳＯ_２−低級アルキル；置換基を有していてもよいシクロアルキル；置換基を有していてもよいアリール；又は、置換基を有していてもよいシクロアルキル、置換基を有していてもよいアリール、置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、ＣＯ−低級アルキル、ＳＯ_２−低級アルキル、ＯＲ’、ＳＲ’、ＮＲ’Ｒ”、ハロゲン、ＮＯ_２、ＣＮ、及びＣＯＯＲ’からなる群から選択される１〜３個の置換基を有していてもよい低級アルキル；但し、Ｒａ及びＲｂの少なくとも一方はＨ以外の基を示す、
又は、ＲａとＲｂは隣接するＮ原子と一体となって、ヘテロ原子としてＮ原子を１〜２個含有する４乃至８員飽和若しくは不飽和ヘテロ環を形成し、該ヘテロ環は、ベンゼン環若しくはシクロアルキル環と縮合していてもよく、架橋を有していてもよく又はスピロ環を形成してもよい、更に、該ヘテロ環は１〜５個の置換基を有していてもよい、
Ｅ：単結合、Ｃ_１−３アルキレン、ビニレン（−Ｃ＝Ｃ−）、エチニレン（−Ｃ≡Ｃ−）、ＣＯ、ＮＲ^７、ＣＨ_２−Ｊ、ＣＯＮＲ^８又はＮＲ^９ＣＯ、
Ｊ：Ｏ、Ｓ、ＮＲ^１０、ＣＯ、ＳＯ又はＳＯ_２、
Ｒ^２：置換基を有していてもよいアリール、置換基を有していてもよいヘテロアリール、置換基を有していてもよいシクロアルキル、置換基を有していてもよいシクロアルケニル、置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、−Ｏ−Ｒ’又は−Ｐ（＝Ｏ）（ＯＲ’）_２
Ｒ^３〜Ｒ^１０、Ｒ’及びＲ”：同一又は異なって、Ｈ又は低級アルキル
【００１１】
但し、以下の化合物を除く。
（１）Ｘ^１，Ｘ^２及びＹがＮ、ＲａとＲｂが隣接するＮ原子と一体となってピペリジノを形成し、Ｒ^３とＲ^４が共にＨ、Ｅが単結合、且つＲ^２がピペリジノ、未置換フェニル，ｐ−（トリフルオロメチル）フェニル、ｐ−クロロフェニル又はｏ−ニトロフェニルである化合物、
（２）Ｘ^１，Ｘ^２及びＹがＮ、ＲａとＲｂが隣接するＮ原子と一体となってピペリジノを形成し、Ｒ^３がＨ，Ｒ^４がメチル、Ｅが単結合、かつＲ^２が未置換フェニル、ｍ−メチルフェニル、ｐ−クロロフェニル、ｍ−メトキシフェニル又はｐ−ニトロフェニルである化合物、
（３）Ｘ^１，Ｘ^２及びＹがＮ、ＲａとＲｂが隣接するＮ原子と一体となって、４−メチル−１−ピペラジニルを形成し、Ｅが単結合、かつＲ^２が未置換フェニル、ｐ−メチルフェニル、ｍ−メチルフェニル、ｐ−メトキシフェニル、ｍ−クロロフェニル、ｐ−クロロフェニル又はｍ−ニトロフェニルである化合物、
（４）Ｘ^１，Ｘ^２及びＹがＮ、Ｒ^２が置換基を有していてもよいイミダゾリル、５−ニトロ−２−フリル又は５−ニトロ−２−チエニルである化合物、
（５）Ｘ^１，Ｘ^２及びＹがＮ、ＲａとＲｂが隣接するＮ原子と一体となって、置換基を有していてもよい１−ピラゾリルを形成し、Ｅが単結合、かつＲ^２が未置換フェニル又はモルホリノである化合物、
（６）Ｘ^１，Ｘ^２及びＹがＮ、ＲａがＨ、Ｒｂがシクロプロピル、Ｅが単結合、かつＲ^２がｐ−（トリフルオロメチル）フェニルである化合物、及び
（７）Ｘ^１，Ｘ^２及びＹがＮ、Ｒａがメチル、Ｒｂが２−ヒドロキシ−プロピル、Ｅが単結合、かつＲ^２が３−ピリジルである化合物。以下同様。）
【００１２】
また、本願には、上記一般式（Ｉ）で示される含窒素複素環化合物又はその製薬学的に許容される塩を有効成分として含む医薬、殊に骨形成促進剤に関する発明が開示される。
【００１３】
【発明の実施の形態】
以下、本発明を詳細に説明する。
本明細書中「低級」とは、特に断らない限り、炭素数１乃至６個を有する直鎖又は分岐状の炭素鎖を意味する。「低級アルキル」としては特にメチル、エチル及びプロピル基が好ましい。なお、本願明細書中において、「低級アルキル」を「Ａｌｋ」と略記する。「Ｃ_１−２アルキレン」としては、好ましくはメチレン及びエチレン基である。
「アリール」は、好ましくはＣ_６−１４単環乃至３環式アリール基である。より好ましくは、フェニル及びナフチル基であり、更に好ましくは、フェニル基である。また、フェニル基にＣ_５−８シクロアルキル環が縮環し、例えば、インダニル又はテトラヒドロナフチル基等を形成していてもよい。「シクロアルキル」は、好ましくはＣ_３−１４シクロアルキル基であり、架橋を有していてもよい。より好ましくはＣ_３−１０シクロアルキル基であり、更に好ましくはシクロペンチル、シクロヘキシル及びシクロヘプチル基である。「シクロアルケニル」は、上記「シクロアルキル」の環に、１又は２個の二重結合を有する基である。
「４乃至８員の単環飽和若しくは一部不飽和ヘテロ環」は、Ｎ，Ｓ，Ｏから選択されるヘテロ原子を１乃至４個含有する４乃至８員単環飽和複素環であり、架橋を有していてもよく、一部不飽和結合を有していてもよい。好ましくは、テトラヒドロピラニル、テトラヒドロフラニル、ピロリジニル、ピペリジル、１，２，３，６−テトラヒドロピリジル、ホモピぺリジニル、ピペラジニル、ホモピペラジニル、キヌクリジニル及びモルホリニル基である。
【００１４】
「ヘテロアリール」としては、Ｎ，Ｓ，Ｏから選択されるヘテロ原子を１乃至４個含有する５乃至６員単環ヘテロアリール基、並びにこれらがベンゼン環若しくは５乃至６員単環ヘテロアリールと縮合した２乃至３環式ヘテロアリール基であり、部分的に飽和されていてもよい。ここに、５乃至６員単環ヘテロアリールとしては、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピリダジニル、ピラジニル及びトリアジニル基が好ましく、２乃至３環式ヘテロアリールとしては、ベンゾフラニル、ベンゾチエニル、ベンゾチアジアゾリル、ベンゾチアゾリル、ベンゾオキサゾリル、ベンゾオキサジアゾリル、ベンゾイミダゾリル、インドリル、イソインドリル、インダゾリル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、ベンゾジオキソリル、ピラジノピリジル、トリアゾロピリジル、ナフチリジニル及びイミダゾピリジル基が好ましい。部分飽和ヘテロアリールとしては、１，２，３，４−テトラヒドロキノリル基等が挙げられる。Ｒ^２におけるヘテロアリールとして、更に好ましい基としては、ピリジル、ピリミジニル、フリル、チエニル、チアゾリル、キノリル、ベンゾフラニル、ベンゾチエニル、インドリル、イミダゾピリジル及びナフチリジニル基であり、特に好ましくは、ピリジル基である。
【００１５】
「置換基を有していてもよいアリール」及び「置換基を有していてもよいヘテロアリール」、「置換基を有していてもよいシクロアルキル」、「置換基を有していてもよいシクロアルケニル」、「置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環」における置換基としては、好ましくは、下記Ｂ群から選択される同一又は異なる１〜５個の置換基であり、より好ましくは、Ａｌｋ、ハロゲノＡｌｋ、ハロゲン、ＮＲ’Ｒ”、ＮＯ_２、ＣＮ、ＯＲ’、−Ｏ−ハロゲノＡｌｋ、ＳＲ’、ＣＯＯＲ’、ＣＯＮＲ’Ｒ”、ＳＯ_２Ａｌｋ、４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、フェニル及びフェノキシから選択される基、特に好ましくは、ハロゲン、ＯＡｌｋ及びＳＡｌｋである。
Ｂ群：Ｅ群から選択される置換基を１〜４個有していてもよいＡｌｋ、ハロゲン、ＮＲ’Ｒ”、ＮＲ’ＣＯ−Ａｌｋ、ＮＯ_２、ＣＮ、ＯＲ’、−Ｏ−（Ｅ群から選択される置換基を１〜４個有するＡｌｋ）、ＳＲ’、−Ｓ−ハロゲノＡｌｋ、−Ｏ−ＣＯＡｌｋ、ＣＯＯＲ’、ＣＯＲ’、ＣＯＮＲ’Ｒ”、ＳＯＡｌｋ、ＳＯ_２Ａｌｋ、ＳＯ_２ＮＲ’Ｒ”、Ｐ（＝Ｏ）（ＯＲ’）_２、−Ｏ−ＣＨ_２−Ｏ−、−Ｏ−（ＣＨ_２）_２−Ｏ−、Ｄ群から選択される置換基を１〜４個有していてもよいアリール、Ｄ群から選択される置換基を１〜４個有していてもよいヘテロアリール、−Ｏ−（Ｄ群から選択される置換基を１〜４個有していてもよいアリール）、Ｄ群から選択される置換基を１〜４個有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、シクロアルキル及び−Ｏ−シクロアルキル。ここに、Ｒ’及びＲ”は前記の通り；「Ｄ群」は、Ａｌｋ、ハロゲン、ハロゲノＡｌｋ、ＮＲ’Ｒ”、ＮＯ_２、ＣＮ、ＯＲ’及びＳＲ’；「Ｅ群」は、ハロゲン、ＮＲ’Ｒ”、ＣＮ、ＣＯＯＲ’、ＯＲ’、ＳＲ’、Ｄ群から選択される置換基を１〜４個有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、Ｄ群から選択される置換基を１〜４個有していてもよいアリール及びＤ群から選択される置換基を１〜４個有していてもよいヘテロアリール；「ハロゲン」は、Ｉ，Ｂｒ、Ｆ及びＣｌ；及び、「ハロゲノＡｌｋ」は、１以上のハロゲン原子で置換された低級アルキル（特に好ましくはＣＦ_３）を、それぞれ示す。
【００１６】
ＲａとＲｂが隣接するＮ原子と一体となって形成する、「ヘテロ原子としてＮ原子を１〜２個含有する４乃至８員飽和若しくは不飽和ヘテロ環」としては、環原子としてＮ原子を１〜２個有する、５員若しくは７員の単環芳香族ヘテロ環又は４乃至８員の単環飽和若しくは一部不飽和ヘテロ環基である。該ヘテロ環は、ベンゼン環若しくはＣ_５−８シクロアルキル環と縮合環を形成してもよく、架橋を有していてもよく、スピロ環を形成していてもよい。好ましくは、ピロリル、イミダゾリル、ピラゾリル、インドリル、イソインドリル、ピロリジニル、ピペリジル、ホモピぺリジニル、ピペラジニル、ピラゾリジニル、イミダゾリジニル、ホモピペラジニル、ペルヒドロアゾシニル、ピロリニル、イミダゾリニル、ピラゾリニル、１，２，３，６−テトラヒドロピリジル、１，２−ジヒドロピリジル、テトラヒドロピリダジニル、テトラヒドロピラジニル、１，４，５，６−テトラヒドロピリミジニル、インドリニル、イソインドリニル、１，２，３，４−テトラヒドロキノリル、１，２，３，４−テトラヒドロイソキノリル、３−アザビシクロ［３．２．１］オクチル、８−アザビシクロ［３．２．１］オクチル、３−アザビシクロ［３．２．２］ノニル、３−アザビシクロ［３．３．１］ノニル、７−アザビシクロ［２．２．１］ヘプチル、イソキヌクリジニル、３−アザビシクロ［３．３．２］デカニル、３−アザスピロ［５．５］ウンデカニル、２−アザスピロ［４．５］デカニル、２−アザスピロ［４．４］ノニル及び８−アザスピロ［４．５］デカニル基等が挙げられる。更に好ましくは、架橋を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環であり、中でも、ピロリジニル、ピペリジル、ホモピぺリジニル、ペルヒドロアゾシニル、１，２，３，６−テトラヒドロピリジル、３−アザビシクロ［３．２．１］オクチル、８−アザビシクロ［３．２．１］オクチル、３−アザビシクロ［３．２．２］ノニル及び３−アザビシクロ［３．３．１］ノニル基が好ましく、ピペリジル基が特に好ましい。
また、該ヘテロ環は、置換基を有していてもよく、この置換基としては前記Ｂ群から選択される１〜５個の置換基が好ましい。更に好ましくは、ハロゲン、ＮＲ’Ｒ”、ＣＮ、（ＣＯＯＲ’、ＯＲ’又はフェニルで置換されていてもよいＡｌｋ）、Ｏ−（ＣＯＯＲ’又はＯＲ’で置換されたＡｌｋ）、ＣＯＯＲ’、ＯＲ’、ＳＲ’、ＣＯＮＲ’Ｒ”及びフェニルから選択される１〜５個の置換基、特に好ましくは、Ａｌｋ、ハロゲン、ＯＲ’及びＣＯＯＲ’から選択される１〜２個の置換基である。
【００１７】
以下、本発明化合物（Ｉ）における好ましい化合物を説明する。
（１）Ｒ^１が−ＮＲａＲｂである化合物
（２）点線が二重結合である化合物、
（３）Ｒ^３及びＲ^４が共にＨである化合物、
（４）Ｘ^１がＮ，Ｘ^２がＮ又はＣＨ及びＹがＮである化合物、より好ましくは、Ｘ^１，Ｘ^２及びＹが全てＮである化合物。
（５）Ｒ^１が−ＮＲａＲｂとして、ベンゼン環若しくはシクロアルキル環と縮合していてもよく、架橋を有していてもよく又はスピロ環を形成してもよく、Ｂ群から選択される１〜５個の置換基を有していてもよい、環ヘテロ原子としてＮ原子を１〜２個含有する４乃至８員飽和若しくは一部不飽和ヘテロ環を形成し；Ｅが、単結合、Ｃ_１−３アルキレン、ビニレン、エチニレン、ＮＨＣＯ、ＣＨ_２ＮＨ、ＣＨ_２Ｏ又はＣＨ_２Ｓであり；Ｒ^２が、Ｂ群から選択される１〜５個の置換基を有していてもよいアリール又はＢ群から選択される１〜５個の置換基を有していてもよいヘテロアリールである化合物。
（６）Ｅが単結合、Ｃ_１−３アルキレン、ビニレン又はエチニレンであり；Ｒ^２が、Ａｌｋ、ハロゲノＡｌｋ、ハロゲン、ＮＲ’Ｒ”、ＮＯ_２、ＣＮ、ＯＲ’、−Ｏ−ハロゲノＡｌｋ、ＳＲ’、ＣＯＯＲ’、ＣＯＮＲ’Ｒ”、ＳＯ_２Ａｌｋ、４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、フェニル及びフェノキシから選択される群から選択される１〜５個の置換基を有するアリール、又は、Ａｌｋ、ハロゲノＡｌｋ、ハロゲン、ＮＲ’Ｒ”、ＮＯ_２、ＣＮ、ＯＲ’、−Ｏ−ハロゲノＡｌｋ、ＳＲ’、ＣＯＯＲ’、ＣＯＮＲ’Ｒ”、ＳＯ_２Ａｌｋ、４乃至８員の単環飽和若しくは一部不飽和ヘテロ環、フェニル及びフェノキシから選択される群から選択される１〜５個の置換基を有するヘテロアリールである化合物。
（７）Ｒ^１が−ＮＲａＲｂとして、環ヘテロ原子としてＮ原子を１個有し架橋を有していてもよく、Ａｌｋ、ハロゲン、ＯＲ’及びＣＯＯＲ’から選択される１〜２個の置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環であり；Ｅが単結合であり；Ｒ^２が、ｍ位にハロゲン、ＯＡｌｋ及びＳＡｌｋから選択される置換基を有するフェニル、又は６位にハロゲン、ＯＡｌｋ及びＳＡｌｋから選択される置換基を有するピリジルである化合物。
【００１８】
本発明において特に好ましい化合物は以下以下の含窒素複素環化合物又はその製薬学的に許容される塩である。
６−アゾカン−１−イル−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−アゼパン−１−イル−３−（６−ブロモピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、３−（３−メトキシフェニル）−６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、３−（３−ブロモフェニル）−６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−アゼパン−１−イル−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−（４−フルオロピペリジン−１−イル）−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−（３−アザビシクロ［３．２．１］オクタン−３−イル）−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−（４，４−ジフルオロピペリジン−１−イル）−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−（３，３−ジフルオロピペリジン−１−イル）−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、６−アゾカン−１−イル−３−（６−ブロモピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン、及び６−（８−アザビシクロ［３．２．１］オクタン−８−イル）−３−（６−ブロモピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン。
【００１９】
本発明の置換基の種類によっては、幾何異性体や互変異性体が存在する場合があるが、本発明にはこれらの異性体の分離したもの、あるいは混合物が包含される。また、本発明化合物は，不斉炭素原子を有する場合があり，これに基づく光学異性体が存在しうる。本発明はこれらの光学異性体の混合物や単離されたものを全て包含する。
【００２０】
本発明化合物（Ｉ）は、酸付加塩又は置換基の種類によっては塩基との塩を形成する場合もある。かかる塩としては、製薬学的に許容される塩であり、好ましくは、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマール酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の金属を含む無機塩基、メチルアミン、エチルアミン、エタノールアミン、リジン、オルニチン等の有機塩基との塩やアンモニウム塩等が挙げられる。
さらに，本発明は，本発明化合物（Ｉ）及びその塩の各種の水和物や溶媒和物及び結晶多形の物質をも包含する。
【００２１】
（製造法）
本発明化合物及びその製薬学的に許容される塩は，その基本骨格あるいは置換基の種類に基づく特徴を利用し，種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護基、すなわち容易に当該官能基に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。しかるのち、必要に応じて保護基を除去し、所望の化合物を得ることができる。このような官能基としては例えば水酸基やカルボキシル基等を挙げることができ、それらの保護基としては例えばグリーン（Ｇｒｅｅｎｅ）及びウッツ（Ｗｕｔｓ）著、「Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ」、第２版に記載の保護基を挙げることができ、これらを反応条件に応じて適宜用いればよい。
【００２２】
以下に本発明化合物の代表的な製造法について説明する。
第１製法
【化３】

（式中、Ｌはハロゲン原子又は有機スルホネート等の常用の脱離基を示す。以下同様。）
本発明化合物（Ｉａ）は、常法のＮ−アルキル化、例えば、アミン誘導体（ＩＩＩ）と、ハロゲン原子又は有機スルホネート等の常用の脱離基を有する化合物（ＩＩ）とを、炭酸カリウム、トリエチルアミン、水素化ナトリウム等の塩基の存在下、又は非存在下で、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、トルエン、テトラヒドロフラン（ＴＨＦ）、アセトニトリル等の不活性溶媒中、又は無溶媒で、冷却下乃至還流下で反応させることによって行うことができる。
【００２３】
第２製法
【化４】

（式中、ＺはＯ又はＳを、Ｒｃは、置換基を有していてもよいアリール、−Ｃ_{１− ２}アルキレン−（置換基を有していてもよいアリール）、−Ｃ_１−２アルキレン−（置換基を有していてもよい４乃至８員の単環飽和若しくは一部不飽和ヘテロ環）又は−Ｃ_１−２アルキレン−ＯＲ’を示す。）
本発明化合物（Ｉｂ）は、常法のエーテル化若しくはチオエーテル化、例えば、アルコール若しくはチオール誘導体（ＩＶ）と、ハロゲン原子又は有機スルホネート等の常用の脱離基を有する化合物（ＩＩ）とを、炭酸カリウム、ｔｅｒｔ−ブチルアミン、水素化ナトリウム等の塩基の存在下、又は非存在下で、ＤＭＦ、トルエン、ＴＨＦ、アセトニトリル等の不活性溶媒中、又は無溶媒で、冷却下乃至還流下で反応させることによって行うことができる。
【００２４】
第３製法
【化５】

（式中、Ａｒは置換基を有していてもよいアリール、置換基を有していてもよいシクロアルキル又は置換基を有していてもよいシクロアルケニルを示す。）
本発明化合物（Ｉｃ）は、ヒドラジン誘導体（ＶＩ）と、ハロゲン原子又は有機スルホネート等の常用の脱離基を有する化合物（Ｖ）とを、酢酸、ｐ−トルエンスルホン酸、塩酸等の酸の存在下、又は非存在下で、メタノール、エタノール、エチレングリコール等の溶媒中、或いは無溶媒で反応させることにより行うことができる。この反応は、室温乃至加熱還流下で行うことができる。
その他の製法
前記第１製法で得られた化合物を、更に、常法の置換基の修飾反応、例えばニトロ基のアミノ基への還元反応、アミド化、スルホンアミド化、Ｎ−アルキル化、エステル化、エステルの加水分解、水酸基のエーテル化、チオエーテルのスルホン化、ハロゲン化、オレフィン化等に付して、所望の置換基を有する本発明化合物を得ることができる。これらの反応は例えば、ＯＲＧＡＮＩＣ　ＦＵＮＣＴＩＯＮＡＬ　ＧＲＯＵＰ　ＰＲＥＰＡＲＡＴＩＯＮＳ　Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ（Ｓａｎｄｌｅｒ，　Ｋａｒｏ著）等に記載の方法に準じて容易に行うことができる。
【００２５】
（原料化合物の製法）
製法ａ
【化６】

本願の原料化合物（ＩＩａ）は、ヒドラジン化合物（ＩＶ）とカルボン酸化合物（Ｖ）とを脱水縮合反応に付しヒドラジド化合物（ＶＩ）とした後、環化することによって製造することができる。
【００２６】
第１工程の脱水縮合反応は常法により行うことができ、例えば、遊離カルボン酸と、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（ＷＳＣＤ）等の縮合剤あるいは１，１’−カルボニルジイミダゾール等のカルボン酸の活性化剤を用いて、又は、カルボン酸の反応性誘導体（例えば、酸クロリド、酸ブロミド等の酸ハライド；酸アジド；メタノール、エタノール、ベンジルアルコール、置換していてもよいフェノール、Ｎ−ヒドロキシスクシンイミド等を用いて調製できる活性エステル；対称酸無水物；アルキル炭酸、ｐ−トルエンスルホン酸等との混合酸無水物等）を用いて容易に行うことができる。
反応は等モルあるいは一方を過剰量用いて、反応に不活性な有機溶媒、例えばピリジン、ＴＨＦ、塩化メチレン、ＤＭＦ、アセトニトリル等の溶媒中にて行われる。反応温度は反応性誘導体の種類によって適宜選択される。反応性誘導体の種類によっては、４−ジメチルアミノピリジン等の塩基を添加することが、反応を促進させる上で有利な場合がある。
第２工程の環化反応は、酢酸、ｐ−トルエンスルホン酸、塩酸等の酸の存在下、又は非存在下で、キシレン、エチレングリコール等の溶媒中、或いは無溶媒で反応させることにより行うことができる。この反応は、室温乃至加熱還流下で行うことができる。
【００２７】
製法ｂ
【化７】

本願の原料化合物（ＸＩＶ）は、化合物（Ｘ）と（ＸＩ）を酢酸等の酸性溶媒中で反応させ化合物（ＸＩＩ）とし、これにオキシ塩化リン等を加え環化反応に付し化合物（ＸＩＩＩ）とし、更に、アルコール溶媒中、パラジウム炭素を触媒としてニトロ基を接触還元することにより製造することができる。反応はいずれも常法により室温乃至加熱還流下で行うことができる。
【００２８】
製法ｃ
【化８】

本願の原料化合物（ＩＩｂ）は、化合物（ＸＶ）をアルコール溶媒中ヒドラジン一水和物と反応させ、化合物（ＸＶＩ）を得た後、酢酸等の酸性溶媒中、臭素を用いた酸化反応により化合物（ＸＶＩＩ）を得、これにオキシ塩化リン等を加えて環化することにより製造することができる。反応は、いずれも常法により、室温乃至加熱還流下で行うことができる。
【００２９】
製法ｄ
【化９】

本願の原料化合物（ＩＩｃ）は、化合物（ＸＶＩＩＩ）と化合物（ＸＩＸ）とをトリエチルアミン等の塩基の存在下、１，４−ジオキサン等の反応に不活性な溶媒中反応させ、化合物（ＸＸ）を得た後、塩化メチレン、ジメチルスルホキシド（ＤＭＳＯ）等の溶媒中、トリエチルアミン等の塩基の存在下で三酸化硫黄ピリジン錯体等の酸化剤を反応させ、化合物（ＸＸＩ）を得、これにトリフルオロ酢酸、無水トリフルオロ酢酸等の酸を加えて環化することにより製造することができる。反応はいずれも常法により、氷冷下乃至加熱還流下で行うことができる。
【００３０】
製法ｅ
【化１０】

本願の原料化合物（ＩＩｄ）は、化合物（ＸＸＩＩ）と化合物（ＸＸＩＩＩ）とをＤＭＦ等の反応に不活性な溶媒中、室温乃至加熱還流下で反応させ、環化することにより製造することができる。
【００３１】
製法ｆ
【化１１】

本願の原料化合物（ＩＩｅ）は、化合物（ＶＩＩ）とイソシアネート化合物（ＸＸＩＶ）とをアセトニトリル等の反応に不活性な溶媒中で縮合させ化合物（ＸＸＶ）を得た後、トリエチルアミン等の塩基の存在下、１，２−ジブロモ−１，１，２，２−テトラクロロエタン及びトリフェニルフォスフィンを加えて環化することにより製造することができる。反応は、常法により、室温乃至加熱還流下で適宜実施できる。
【００３２】
上記各製法により得られた反応生成物は，遊離化合物，その塩、水和物あるいは各種の溶媒和物として単離され精製される。塩は通常の造塩反応に付すことにより製造できる。単離，精製は，抽出，濃縮，留去，結晶化，濾過，再結晶，各種クロマトグラフィー等通常の化学操作を適用して行われる。各種異性体は異性体間の物理化学的な差を利用して常法により単離できる。例えば、光学異性体は一般的な光学分割法、例えば分別結晶化又はクロマトグラフィー等により分離できる。また、光学異性体は、適当な光学活性な原料化合物より合成することもできる。
【００３３】
【発明の効果】
本発明化合物は、骨芽細胞による骨形成を促進させ骨形成を促進する作用を有しており、骨吸収能に比して骨形成能が低下したことに伴う代謝性骨疾患の予防若しくは治療に有用である。このような代謝性骨疾患としては、骨粗鬆症、線維性骨炎（副甲状腺機能亢進症）、骨軟化症、更に全身性の骨代謝パラメーターに影響を与えるページェット病が挙げられる。特に骨形成能が低下した老人性骨粗鬆症に有用である。
また、本発明の骨形成促進剤は、整形外科領域の骨折、骨欠損及び変形性関節症などの骨疾患の治癒促進、及び歯科領域における歯周病治療や人工歯根の安定等にも応用が期待できる。
【００３４】
骨芽細胞の表現形質としては、アルカリホスファターゼ（ＡＬＰ）活性、骨基質蛋白質（コラーゲン、オステオカルシン、オステオネクチン、オステオポンチン等）の産生、活性型ビタミンＤ_３　レセプター、副甲状腺ホルモンレセプター、エストロゲンレセプター、アンドロゲンレセプターの存在が挙げられる（モレキュラー・メディシン、３０巻、１０号、１２３２　（１９９３））。そして、ＡＬＰは骨芽細胞の機能発現初期より上昇する（ジャーナル・オブ・セルラー・フィジオロジー、１４３巻、４２０　（１９９０））。骨芽細胞による骨形成に対するＡＬＰの役割は、骨形成部局所のリン酸イオン濃度を押し上げること及び石灰化阻害物質であるピロリン酸を分解することであるとされている（細胞工学、１３巻、１２号、１０６２　（１９９４））。またＡＬＰとコラーゲンシートを共有結合させたものをラットの皮下に移植すると石灰化が起こることが示されている（Ｊ．　Ｃｌｉｎ．　Ｉｎｖｅｓｔ．，　８９，　１９７４　（１９９２））。従って、骨芽細胞のＡＬＰ活性上昇は骨形成促進の指標として評価できる。
【００３５】
以下、本発明化合物の薬理作用を証明するための試験及び結果を示す。
試験例１：マウス骨芽細胞株におけるアルカリフォスファターゼ （ＡＬＰ） 活性測定
マウス由来骨芽細胞株ＭＣ３Ｔ３−Ｅ１を５％ウシ胎仔血清（ＦＢＳ：ｆｅｔａｌ　ｂｏｖｉｎｅ　ｓｅｒｕｍ）含有α−最小必須培地（ＭＥＭ：ｍｉｎｉｍｕｍ　ｅｓｓｅｎｔｉａｌ　ｍｅｄｉｕｍ）中で９６穴プレートに３０００ｃｅｌｌｓ／ｗｅｌｌの濃度で播種し、４〜６時間培養した。接着した細胞に、ジメチルスルホキシド（ＤＭＳＯ）に溶解した試験化合物を添加し（ＤＭＳＯ終濃度０．５％）、さらに３日間培養した。細胞をリン酸緩衝生理食塩水で洗浄後、基質を添加し、３７℃で１０−１５分間インキュベートした。０．５Ｍの水酸化ナトリウムを加えて反応を停止させ、４０５ｎｍ（参照波長４９２ｎｍ）の吸光度を測定し、対照群を１００％として、これに対する％値として、ＡＬＰ活性を算出した。なお、上記測定法はＬｏｗｒｙらの方法（Ｊｏｕｒｎａｌ　ｏｆ　Ｂｉｏｌｏｇｉｃａｌ　Ｃｈｅｍｉｓｔｒｙ、２０７巻、１９頁（１９５４年））を参考にして行った。
本発明の実施例３，９，１８，３０，３３，３４，３９，４０，４７，４８，５１，５７，５８，６２，６５，６６，７１，７６，８３，１０３，１０８，１１５，１１８，１１９，１２６，１３１，１３２，１３３，１３４，１４３，１４４，１４５，１４６，　１４７，１５５，１６２，１６９，１７９，１８３，１８４，１８５，２０１，２０４，２０７及び２０９の化合物は、３００ｎＭの濃度において対照群に対して３００％以上のＡＬＰ活性を有していた。
【００３６】
試験例２：ラット局所投与における骨形成促進試験
本発明の実施例３３の化合物（１、１０、又は１００μｇ）を，鉱物油０．１ｍｌに分散し、エーテル麻酔下１０週齢雄性Ｗｉｓｔａｒ　ラット（ｎ＝６）右側頭部皮下に２５Ｇ注射針を装着した１　ｍｌシリンジを用いて１日１回、１０日間連日投与した。対照としては、鉱物油０．１ｍｌのみを１日１回、１０日間連日投与したラットを用いた。投与開始１１日目からは休薬し、同１８日目にラットを屠殺し頭蓋冠を取り出した。屠殺に先立ち、投与開始１０日目にテトラサイクリン（２５ｍｇ／ｋｇ）を、また投与開始１６日目にカルセイン（２０ｍｇ／ｋｇ）を背部皮下に投与し、骨標識を施した。取り出した頭蓋冠を７０％エタノールで固定した後に、常法に則り前顎断の切片を作製し、骨形態計測を行った。本発明化合物投与群並びに対照群の類骨幅並びに石灰化速度を図１及び図２に示す。
本発明化合物の投与により、有意な類骨幅及び石灰化速度の増大が観察され、本発明化合物の優れた骨形成促進活性が確認された。
【００３７】
本発明化合物（Ｉ）又はこれらの製薬学的に許容される塩を有効成分とする医薬は，一般式（Ｉ）又はこれらの製薬学的に許容される塩の１種又は２種以上と、通常製剤化に用いられる、薬剤用担体、賦形剤，その他添加剤を用いて、通常使用されている方法によって調製することができる。投与は錠剤，丸剤，カプセル剤，顆粒剤，散剤，液剤、吸入剤等による経口投与，又は，静注，筋注等の注射剤，坐剤経皮用液剤、軟膏剤、経皮用貼付剤等による非経口投与のいずれの形態であってもよい。
【００３８】
本発明による経口投与のための固体組成物としては，錠剤，散剤，顆粒剤等が用いられる。このような固体組成物においては，ひとつ又はそれ以上の活性物質が，少なくともひとつの不活性な希釈剤，例えば乳糖，マンニトール，ブドウ糖，ヒドロキシプロピルセルロース，微結晶セルロース，デンプン，ポリビニルピロリドン，メタケイ酸アルミン酸マグネシウムと混合される。組成物は，常法に従って，不活性な希釈剤以外の添加剤，例えばステアリン酸マグネシウムのような潤滑剤や繊維素グリコール酸カルシウムのような崩壊剤，安定化剤，グルタミン酸又はアスパラギン酸のような溶解補助剤を含有していてもよい。錠剤又は丸剤は必要によりショ糖，ゼラチン，ヒドロキシプロピルセルロース，ヒドロキシプロピルメチルセルロースフタレートなどの糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
【００３９】
経口投与のための液体組成物は，薬剤的に許容される乳濁剤，溶液剤，懸濁剤，シロップ剤，エリキシル剤等を含み，一般的に用いられる不活性な希釈剤，例えば精製水，エタノールを含む。この組成物は不活性な希釈剤以外に湿潤剤，懸濁剤のような補助剤，甘味剤，風味剤，芳香剤，防腐剤を含有していてもよい。非経口投与のための注射剤としては，無菌の水性又は非水性の溶液剤，懸濁剤，乳濁剤を含有する。水性の溶液剤，懸濁剤としては，例えば注射用蒸留水及び生理食塩液が含まれる。非水溶性の溶液剤，懸濁剤としては，例えばプロピレングリコール，ポリエチレングリコール，オリーブ油のような植物油，エタノールのようなアルコール類，ポリソルベート８０（商品名）等がある。このような組成物は，さらに防腐剤，湿潤剤，乳化剤，分散剤，安定化剤，溶解補助剤（例えば，グルタミン酸，アスパラギン酸）のような補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過，殺菌剤の配合又は照射によって無菌化される。これらはまた無菌の固体組成物を製造し，使用前に無菌水又は無菌の注射用溶媒に溶解して使用することもできる。
通常経口投与の場合、１日の投与量は，体重当たり約０．００１から１０ｍｇ／ｋｇ、好ましくは０．０１〜５ｍｇ／ｋｇが適当であり，これを１回であるいは２乃至４回に分けて投与する。静脈投与される場合は、１日の投与量は，体重当たり約０．０００１から１ｍｇ／ｋｇが適当で、１日１回乃至複数に分けて投与する。投与量は症状，年令，性別等を考慮して個々の場合に応じて適宜決定される。
【００４０】
【実施例】
以下，実施例に基づき本発明を更に詳細に説明する。本発明化合物は下記実施例に記載の化合物に限定されるものではない。原料化合物の製造法を参考例に示す。なお、文中の略号は、Ｄａｔ：物理化学的性状、Ｆ：ＦＡＢ−ＭＳ　（Ｍ＋Ｈ）^＋を示し、その他の略号は前記の通りである。
【００４１】
参考例１：（６−クロロピリダジン−３−イル）ヒドラジン、４−ニトロ安息香酸、ＷＳＣＤ塩酸塩及びＴＨＦの混合物を室温で２時間攪拌した。反応液に水を加え、析出した沈殿物を濾取し、水及びジエチルエーテルで洗浄し、Ｎ’−（６−クロロピリダジン−３−イル）−４−ニトロベンゾヒドラジドを得た。これに酢酸を加え、１１０℃で２時間攪拌した後、反応液を減圧下で濃縮し、得られた粗結晶をエタノールで洗浄し、６−クロロ−３−（４−ニトロフェニル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジンを得た。Ｄａｔ（Ｆ：２７６）
参考例２：（６−クロロピリダジン−３−イル）ヒドラジンとトリエチルアミンのＴＨＦ溶液に、氷冷下で３−シアノベンゾイルクロリドを加え、室温で１時間攪拌した。反応液に水を加え、析出した沈殿物を濾取し、水及びジエチルエーテルで洗浄し、Ｎ’−（６−クロロピリダジン−３−イル）−３−シアノベンゾヒドラジドを得た。これに酢酸を加え、１１０℃で２時間攪拌した後、反応液を減圧下濃縮し、得られた粗結晶をエタノールで洗浄し、３−（６−クロロ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）ベンゾニトリルを得た。Ｄａｔ（Ｆ：２５６）
【００４２】
参考例３：（６−クロロピリダジン−３−イル）ヒドラジン、３−ジメチルアミノ安息香酸、ＷＳＣＤ塩酸塩及びＴＨＦの混合物を室温で２時間攪拌した。反応液に水を加え、析出した沈殿物を濾取し、水及びジイソプロピルエーテルで洗浄し、Ｎ’−（６−クロロピリダジン−３−イル）−３−ジメチルアミノベンゾヒドラジドを得た。これにエチレングリコールを加え、１６０℃で４時間攪拌した。室温にまで放冷した後、常法により精製して、６−クロロ−３−（３−ジメチルアミノフェニル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジンを得た。Ｄａｔ（Ｆ：２７４）
参考例４：３−メトキシフェニルイソシアネートと３−クロロ−６−ヒドラジノピリダジンのアセトニトリル溶液を室温で３０分間攪拌した後、１，２−ジブロモ−１，１，２，２−テトラクロロエタンを加え、更に室温で２時間攪拌した。この反応溶液に氷冷下トリエチルアミンとトリフェニルホスフィンを加え、室温で３日間攪拌した後、反応溶液を減圧下濃縮し、常法により精製して、６−クロロ−Ｎ−（３−メトキシフェニル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−アミンを得た。Ｄａｔ（Ｆ：２７６）
参考例５：３，６−ジクロロ−４−メチルピリダジン、ヒドラジン１水和物、トリエチルアミン及び１，４−ジオキサンの混合物を１００℃で８時間攪拌した後、常法により精製し、３−クロロ−６−ヒドラジノ−４−メチルピリダジン及び６−クロロ−３−ヒドラジノ−４−メチルピリダジンの混合物を得た。これに３−メトキシ安息香酸、ＷＳＣＤ塩酸塩及び塩化メチレンを加え、室温で５時間攪拌した後、常法により精製し、Ｎ’−（６−クロロ−５−メチルピリダジン−３−イル）−３−メトキシベンゾヒドラジドとＮ’−（６−クロロ−４−メチルピリダジン−３−イル）−３−メトキシベンゾヒドラジドの混合物を得た。これに酢酸を加え、１００℃で１０時間攪拌した後、反応液を減圧下濃縮した後、常法により精製し、６−クロロ−３−（３−メトキシフェニル）−７−メチル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジンを得た。Ｄａｔ（Ｆ：２７５）
【００４３】
参考例６：２−クロロ−５−ニトロピリジン、３−メトキシベンゾヒドラジド及び酢酸の混合物を加熱還流下１８時間攪拌した後、常法により精製して、３−メトキシ−Ｎ’−（５−ニトロピリジン−２−イル）ベンゾヒドラジドを得た。これにオキシ塩化リンを加え，１００℃で７時間攪拌した後、常法により精製して、３−（３−メトキシフェニル）−６−ニトロ−１，２，４−トリアゾロ［４，３−ａ］ピリジンを得た。これにエタノール及び１０％パラジウム−炭素を加え，水素雰囲気下常温常圧で５時間攪拌した後、常法により精製して、３−（３−メトキシフェニル）−１，２，４−トリアゾロ［４，３−ａ］ピリジン−６−アミンを得た。Ｄａｔ（Ｆ：２４０）
参考例７：２−（３−メトキシフェニル）−１，３−オキサゾール−５（４Ｈ）−オン、トリエチルアミン、４−（ジメチルアミノ）ピリジン及びＴＨＦの混合物に、氷冷下４−クロロ−４−オキソ酪酸エチルのＴＨＦ溶液を加え，氷冷から室温で２時間攪拌した後、反応液を減圧下で濃縮した。得られた残渣に水を加え、加熱還流下３時間攪拌した後、常法により精製して、５−［（３−メトキシベンゾイル）アミノ］−４−オキソペンタン酸エチルを得た。これにヒドラジン１水和物及びエタノールを加え，加熱還流下１時間攪拌した後，常法により精製して、３−メトキシ−Ｎ−［（６−オキソ−１，４，５，６−テトラヒドロピリダジン−３−イル）メチル］ベンズアミドを得た。これに酢酸を加え，臭素を徐々に滴下した後，５０℃で２時間攪拌し、反応液を減圧下濃縮した。得られた残渣を常法により精製して、３−メトキシ−Ｎ−［（６−オキソ−１，６−ジヒドロピリダジン−３−イル）メチル］ベンズアミドを得た。これにオキシ塩化リンを加えて，１００℃で２時間攪拌した後、常法により精製して、２−クロロ−７−（３−メトキシフェニル）−イミダゾ［１，５−ｂ］ピリダジンを得た。Ｄａｔ（Ｆ：２６０）
参考例８：Ｎ’−（６−クロロピリダジン−３イル）−Ｎ，Ｎ−ジメチルホルムアミジンのＤＭＦ溶液に３’−メトキシフェナシルブロミドを加え、加熱還流下で３時間攪拌した。反応液を室温まで冷却後、常法により精製し、（６−クロロイミダゾ［１，２−ｂ］ピリダジン−３−イル）−（３−メトキシフェニル）メタノンを得た。Ｄａｔ（Ｆ：２８８）
【００４４】
参考例９：６−メトキシピリジン−２−カルバルデヒドのメタノール溶液に、ニトロメタン及びナトリウムメトキシドのメタノール溶液を加え、室温で１時間攪拌した。反応液を酢酸で中和後、常法により精製し、１−（６−メトキシピリジン−２−イル）−２−ニトロエタノールを得た。これをジエチルエーテルに溶解し、室温で水素化リチウムアルミニウムのジエチルエーテル懸濁液に滴下した。室温で１時間攪拌した後、常法により精製し、２−アミノ−１−（６−メトキシピリジン−２−イル）エタノールを得た。これに１，４−ジオキサン、トリエチルアミン及び２，６−ジクロロピリダジンを加え、加熱還流下で２１時間攪拌した後、常法により精製し、２−［（６−クロロピリダジン−３−イル）アミノ］−１−（６−メトキシピリジン−２−イル）エタノールを得た。これを塩化メチレンに溶解し、氷冷下ＤＭＳＯ、トリエチルアミン及び三酸化硫黄ピリジン錯塩を加え、室温で２時間攪拌した後、常法により精製し、２−［（６−クロロピリダジン−３−イル）アミノ］−１−（６−メトキシピリジン−２−イル）エタノンを得た。これにトリフルオロ酢酸、無水トリフルオロ酢酸を加え、室温で１３時間攪拌した後、反応液を減圧下濃縮した。得られた残渣を常法により精製し、６−クロロ−３−（６−メトキシピリジン−２−イル）イミダゾ［１，２−ｂ］ピリダジンを得た。Ｄａｔ（Ｆ：２６１）
参考例１と同様にして、後記表１〜４に示される参考例１０〜８８の化合物を、参考例８と同様にして参考例８９の化合物を、参考例９と同様にして参考例９０及び９１の化合物をそれぞれ得た。
【００４５】
実施例１：３−（６−クロロ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）ベンゾニトリル（４５０ｍｇ）及びピペリジン（５ｍｌ）の混合物を、加熱還流下２時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をクロロホルムで抽出した。抽出液を飽和塩化アンモニウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］ベンゾニトリル（４３５ｍｇ）を微黄色結晶として得た。
実施例２：６０％水素化ナトリウム（３０ｍｇ）のＤＭＦ（５ｍｌ）溶液に、氷冷下ピラゾール（５０ｍｇ）を加えて２０分間攪拌した後、６−クロロ−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（１４０ｍｇ）を加え、８０℃で４時間攪拌した。反応液に水を加え、酢酸エチルで希釈した。有機層を５％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、３−（６−メトキシピリジン−２−イル）−６−（１Ｈ−ピラゾール−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（３９ｍｇ）を微黄色結晶として得た。
実施例３：Ｎ−シクロペンチル−３−（３−メトキシフェニル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−アミン（３００ｍｇ）のＤＭＦ（５ｍｌ）溶液に氷冷下６０％水素化ナトリウム（４４ｍｇ）を加え、氷冷から室温で１時間攪拌した後、ヨウ化メチル（６８μｌ）を加え，さらに２時間攪拌した。反応混合物に水を加えた後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後，減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝２０：１）で精製した後、酢酸エチルから再結晶し、Ｎ−シクロペンチル−３−（３−メトキシフェニル）−Ｎ−メチル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−アミン（１４５ｍｇ）を淡黄色結晶として得た。
【００４６】
実施例４：水酸化カリウム（９８ｍｇ）とＤＭＳＯ（５ｍｌ）の混合物に６−アゼパン−１−イル−３−（１Ｈ−インドール−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（５０１ｍｇ）を加え、室温にて３０分攪拌した後、ヨウ化メチル（０．１５ｍｌ）を加え、さらに２時間室温にて攪拌した。反応液に水を加え、析出した固体を濾取し、水−メタノール混合溶媒で洗浄後、シリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝９９：１）で精製した。得られた粗結晶をエタノールから再結晶し、６−アゼパン−１−イル−３−（１−メチルインドール−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（４０ｍｇ）を無色結晶として得た。
実施例５：３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］アニリン（１８０ｍｇ）と無水酢酸（３ｍｌ）の混合物を室温で６時間攪拌した。反応液を減圧下で濃縮し、得られた粗結晶をジエチルエーテルで洗浄することにより、３’−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］アセトアニリド（１９０ｍｇ）を無色結晶として得た。
実施例６：６−ピペリジン−１−イル−３−ピペリジン−３−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（６７０ｍｇ）、トリエチルアミン（３６０ｍｇ）及び塩化メチレン（１５ｍｌ）の混合溶液にメタンスルホニルクロリド（３２０ｍｇ）を加え、室温で８時間攪拌した。反応液を減圧下で濃縮し、得られた残渣を酢酸エチルで抽出した。抽出液を水と飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、３−（１−メタンスルホニルピペリジン−３−イル）−６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（２３０ｍｇ）を無色結晶として得た。
【００４７】
実施例７：６−クロロ−３−（３−メトキシフェニル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（８８０ｍｇ）、フェノール（３５０ｍｇ）、炭酸カリウム（７００ｍｇ）及びＤＭＦ（１０ｍｌ）の混合物を８０℃で１０時間攪拌した。反応液に水を加え、酢酸エチルで希釈した。有機層を水、１Ｍ水酸化ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、３−（３−メトキシフェニル）−６−フェノキシ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（８００ｍｇ）を無色結晶として得た。
実施例８：２−ピペリジン−１−イルエタノール（０．１３ｇ）のＤＭＦ（５ｍｌ）溶液に、氷冷下６０％水素化ナトリウム（５０ｍｇ）を加え、室温にて３０分間攪拌した後、６−クロロ−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（０．２２ｇ）を加え、室温にて一晩攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残渣のエタノール溶液（１０ｍｌ）に４Ｍ塩化水素−１，４−ジオキサン溶液（１ｍｌ）を加え、減圧下濃縮し、得られた粗結晶をエタノール−酢酸エチルから再結晶し、３−（６−メトキシピリジン−２−イル）−６−（２−ピペリジン−１−イルエトキシ）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン・２塩酸塩（０．１２ｇ）を無色結晶として得た。
実施例９：６−アゾカン−１−イル−３−（６−クロロピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（３６０ｍｇ）、ナトリウムメトキシド（５７０ｍｇ）及びトルエン（２０ｍｌ）の混合物を加熱還流下３時間攪拌した。室温にまで放冷後、反応液を減圧下で濃縮し、得られた残渣を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた粗結晶をジエチルエーテルで洗浄し、６−アゾカン−１−イル−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（２９０ｍｇ）を淡黄色結晶として得た。
【００４８】
実施例１０：３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］フェノール（３００ｍｇ）及びＤＭＦ（５ｍｌ）の混合物に、氷冷下で６０％水素化ナトリウム（４９ｍｇ）を加え、３０分間攪拌した後、氷冷下でヨウ化エチル（０．１０ｍｌ）を加え、再び３０分間攪拌した。反応液を減圧下濃縮し、得られた残渣を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝５０：１）で精製した後、エタノールから再結晶し、３−（３−エトキシフェニル）−６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（１８７ｍｇ）を褐色結晶として得た。
実施例１１：６−クロロ−３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（０．２２ｇ）、ｔｅｒｔ−ブチルアミン（２ｍｌ）、エチレングリコール（２ｍｌ）の混合物を１００℃にて終夜攪拌した。これを室温まで冷却し、析出した固体を濾取し、エタノール及びジエチルエーテルで順次洗浄後、乾燥することにより、２−｛［３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−イル］オキシエタノール（７５ｍｇ）を無色結晶として得た。
実施例１２：３−（３−ニトロフェニル）−６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（５６０ｍｇ）、１０％パラジウム−炭素（６０ｍｇ）及びエタノール（４０ｍｌ）の混合物に、室温で蟻酸アンモニウム（８７０ｍｇ）を加え、５０℃で６時間攪拌した。室温にまで放冷後、触媒を濾去し、濾液を減圧下濃縮した。得られた粗結晶をエタノール−水（９：１）から再結晶し、３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］アニリン（２８０ｍｇ）を無色結晶として得た。
【００４９】
実施例１３：３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］安息香酸メチル（８０３ｍｇ）と１Ｍ水酸化ナトリウム水溶液（２０ｍｌ）の混合物を１００℃で３０分間攪拌した。反応液に氷冷下で１Ｍ塩酸（２０ｍｌ）を加え、析出した固体を濾取し、水で洗浄した。得られた粗結晶をエタノールから再結晶し、３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］安息香酸（５６０ｍｇ）を無色結晶として得た。
実施例１４：３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］安息香酸（４３０ｍｇ）、触媒量のＤＭＦ及びＴＨＦ（１０ｍｌ）の混合溶液に、氷冷下で塩化オキザリル（０．４４ｍｌ）を加え、室温で２時間攪拌した後、氷冷下でアンモニアガスを１５分間通じた。反応液を減圧下濃縮し、得られた残渣にクロロホルム−メタノール（１０：１）を加え、不溶物を濾去した。濾液を減圧下濃縮し、得られた粗結晶をエタノールから再結晶し、３−［６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル］ベンズアミド（２４２ｍｇ）を微褐色結晶として得た。
【００５０】
実施例１５：３−クロロ−６−フェニルピリダジン（２．２９ｇ）、３−メトキシベンゾイルヒドラジン（１．６６ｇ）及び酢酸（２０ｍｌ）の混合物を１１０℃で１日攪拌した。室温にまで放冷後、反応液を減圧下濃縮し、得られた残渣を飽和炭酸カリウム水溶液で中和し、酢酸エチルで抽出した。抽出液を水と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、３−（３−メトキシフェニル）−６−フェニル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（１．１８ｇ）を無色結晶として得た。
実施例１６：３−［３−（メチルスルファニル）フェニル］−６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（５５０ｍｇ）の塩化メチレン（３０ｍｌ）溶液に、室温で３−クロロ過安息香酸（１．２５ｇ）を加えて１３時間攪拌した。反応液に水を加え、塩化メチレンで希釈した。有機層を水、１Ｍ水酸化ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝９８：２）で精製した後、エタノールで洗浄し、３−［３−（メチルスルホニル）フェニル］−６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（２５０ｍｇ）を無色結晶として得た。
【００５１】
実施例１７：濃硫酸（１．５ｍｌ）及び水（３ｍｌ）の混合液を−５℃に冷却し、４−（６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）−１，３−チアゾール−２−アミン（０．９０ｇ）、硫酸銅（ＩＩ）（１．５０ｇ）臭化ナトリウム（０．６２ｇ）を順次加え０℃にて５分間攪拌した後、亜硝酸ナトリウム（０．２５ｇ）の水溶液（１．６ｍｌ）を滴下し、室温にて終夜攪拌した。反応液に水、クロロホルム及び２−プロパノールを加え、不溶物を濾去した。得られた有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝２０：１）で精製し、得られた粗結晶をエタノール−ジエチルエーテルから再結晶することにより、３−（２−ブロモ−１，３−チアゾール−４−イル）−６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（７５ｍｇ）を淡黄色結晶として得た。
実施例１８：６−（６−アゼパン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）ピリジン−２−オール（７００ｍｇ）及び三臭化リン（７ｍｌ）の混合物を１３０℃で６時間攪拌した。室温にまで放冷し、氷水を加え、飽和炭酸カリウム水溶液で中和した後、クロロホルムで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝９８：２）で精製した後、エタノールから再結晶し、６−アゼパン−１−イル−３−（６−ブロモピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（２４０ｍｇ）を無色結晶として得た。
【００５２】
実施例１９：ジエチル　［（６−アゼパン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）メチル］ホスホネート（３６７ｍｇ）のＴＨＦ（１０ｍｌ）溶液に、氷冷下カリウム　ｔｅｒｔ−ブトキシド（１２７ｍｇ）を加え、室温にて４０分間攪拌した。得られた赤色溶液に２−ブロモベンズアルデヒド（０．１２８ｍｌ）を加え、室温にて更に１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた白色固体をメタノールから再結晶し、６−アゼパン−１−イル−３−［（Ｅ）−２−（２−ブロモフェニル）ビニル］−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（１５２ｍｇ）を無色結晶として得た。
実施例２０：エチル　６−クロロ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−カルボキシレート（３．００ｇ）及びヘキサメチレンイミン（１０ｍｌ）の混合物を１００℃にて２時間攪拌した。反応液を減圧下濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝３０：１）で精製し、得られた粗結晶をエタノール及びジエチルエーテルから再結晶することにより、３−（アゼパン−１−イルカルボニル）−６−アゼパン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（０．２３ｇ）を無色結晶として得た。
【００５３】
実施例２１：　１−［３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピペリジン−６−イル］ピペリジン−３−オール（０．９４ｇ）のクロロホルム溶液（１２ｍｌ）にピリジン（３ｍｌ）及び４−トルエンスルホニルクロリド（１．１４ｇ）を加え、室温で３晩攪拌した後、反応液をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝３０：１）により精製し、１−［３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−イル］ピペリジン−３−イル　４−トルエンスルホナート（１．０２ｇ）を得た。本化合物（０．３４ｇ）をＤＭＳＯ（３ｍｌ）に溶解し、アジ化ナトリウム（０．１４ｇ）を加え、１００℃で一晩攪拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、次いで無水硫酸マグネシウムで乾燥後、減圧下濃縮した。得られた残さをシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝５０：１）により精製し、６−（３−アジドピペリジン−１−イル）１−［３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（０．２２ｇ）を得た。Ｄａｔ（Ｆ：３５２）。この化合物（０．２１ｇ）のＴＨＦ溶液（３ｍｌ）にトリフェニルホスフィン（０．２０ｇ）を加え、室温にて終夜攪拌した。反応液に水（１ｍｌ）を加え、６０℃にて６時間攪拌した後、室温まで冷却し、炭酸水素ナトリウム水溶液を加え、クロロホルム及び２−プロパノールの混合溶媒にて抽出した。得られた有機層を無水硫酸マグネシウムで乾燥後、減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール：２９％アンモニア水＝３０：１：０．１）で精製し、ジエチルエーテル−酢酸エチルにて洗浄することにより、１−［３−（６−メトキシピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−イル］ピペリジン−３−アミン（９０ｍｇ）を無色非晶性物質として得た。
実施例２２：　１−［（ベンジルオキシ）カルボニル］ピペリジン−３−カルボン酸（２．４４ｇ）、３−クロロ−６−ヒドラジノピリダジン（１．３４ｇ）、ＷＳＣＤ塩酸塩（２．１３ｇ）及び塩化メチレン（６０ｍｌ）の混合物を室温で１６時間攪拌した。反応溶液を減圧下濃縮し、酢酸エチルで抽出した。抽出液を水と飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣に酢酸（８０ｍｌ）を加え、１１０℃で２日間攪拌後、溶媒を減圧下留去した。得られた粗結晶をエタノールで洗浄し、ピペリジン（１０ｍｌ）中、加熱還流下で３時間攪拌した。反応溶液を減圧下濃縮し、シリカゲルカラムクロマトグラフィー（溶出液：クロロホルム：メタノール＝９７：３）で精製した。得られた無色固体にエタノール（４０ｍｌ）と１０％パラジウム−炭素（１５０ｍｇ）を加え、水素雰囲気下室温で６時間攪拌した後、触媒を濾去した。得られた濾液を減圧下濃縮することにより、６−ピペリジン−１−イル−３−ピペリジン−３−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（１．１８ｇ）を無色非晶性物質として得た。
【００５４】
実施例２３：　エチル　２−アミノチアゾール−４−カルボキシレート（４．５６ｇ）のＴＨＦ溶液（２００ｍｌ）に１Ｍ水酸化ナトリウム水溶液（３０ｍｌ）を加え、室温で３時間攪拌した。反応液に１Ｍ塩酸（３０ｍｌ）を加え、濃縮した後、得られた残渣をＤＭＦ（５０ｍｌ）に溶解し、これに６−クロロピリダジン−３−イルヒドラジン（３．８３ｇ）及びＷＳＣＤ塩酸塩（６．０９ｇ）を加え、室温にて攪拌した。反応液に水を加え、析出した沈殿物を濾取し、水及びジエチルエーテルで洗浄し、これに酢酸（３０ｍｌ）を加え、加熱還流した後、反応液を減圧下濃縮した。残さに飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、及び飽和食塩水で洗浄し、次いで無水硫酸マグネシウムで乾燥後、減圧下濃縮した。これにピペリジン（１０ｍｌ）を加え、１００℃で加熱し、反応液を減圧下濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝３０：１）により精製し、３−（２’−アミノチアゾール−４−イル）−６−（ピペリジン−１−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（０．９２ｇ）を黄色固体として得た。
実施例２４：　６−ヒドラジノ−Ｎ−メチル−Ｎ−フェニルピリダジン−３−アミン（１．１４ｇ）の塩化メチレン溶液（１０ｍｌ）に６−クロロピコリン酸（０．８３ｇ）及びＷＳＣＤ塩酸塩（１．２２ｇ）を加え、室温にて終夜攪拌した。反応液をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム）により精製し、６−クロロ−Ｎ’−｛６−［メチル（フェニル）アミノ］ピリダジン−３−イル｝ピリジン−２−カルボヒドラジド（０．５７ｇ）を得た。本化合物（０．５６ｇ）をキシレン（２０ｍｌ）中、１５０℃で終夜攪拌し、反応液を濃縮し、３−（６−クロロピリジン−２−イル）−Ｎ−メチル−Ｎ−フェニル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−６−アミン（０．５４ｇ）を無色固体として得た。
【００５５】
実施例２５：　６−クロロ−３−（６−クロロピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（６２０ｍｇ）、ヘプタメチレンイミン（１．３２ｇ）及び１，４−ジオキサン（２０ｍｌ）の混合物を１００℃で９時間攪拌した。室温にまで放冷後、反応溶液を減圧下濃縮し、得られた残渣を酢酸エチルで抽出した。抽出液を５％クエン酸水溶液、水、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた粗結晶をエタノールから再結晶し、６−アゾカン−１−イル−３−（６−クロロピリジン−２−イル）−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（３７０ｍｇ）を灰白色結晶として得た。
実施例２６：　６−（６−クロロ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）ピリジン−２−オール（９６０ｍｇ）とピペリジン（１０ｍｌ）の混合物を１００℃で３時間攪拌した。室温にまで放冷後、反応溶液を減圧下濃縮し、得られた結晶性残渣をエタノールで再結晶することにより、６−（６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン−３−イル）ピリジン−２−オール（８２０ｍｇ）を灰白色結晶として得た。
【００５６】
実施例２７：６−アミノ−３−（３−メトキシフェニル）−１，２，４−トリアゾロ［４，３−ａ］ピリジン（４１０ｍｇ）のＴＨＦ（５ｍｌ）溶液に、−５〜０℃で５０％グルタルアルデヒド水溶液（０．３３ｍｌ）、水（０．３３ｍｌ）３Ｍ硫酸２．２ｍｌ、メタノール（３．８ｍｌ）、ＴＨＦ（２．５ｍｌ）の混合物及び水素化ホウ素ナトリウム（１５０ｍｇ）を加え、室温で２時間攪拌した。反応混合物に、１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝１００：１）で精製した。得られた残渣を酢酸エチルに溶解した後、４Ｍ塩化水素−酢酸エチル溶液（２ｍｌ）を加え、室温で３０分間攪拌した。混合物を減圧下濃縮し、得られた粗結晶をアセトニトリルから再結晶し、３−（３−メトキシフェニル）−６−ピペリジン−１−イル−１，２，４−トリアゾロ［４，３−ａ］ピリジン・２塩酸塩（２１ｍｇ）を褐色固体として得た。
実施例２８：６−アゼパン−１−イル−３−［（Ｅ）−２−（２−メトキシフェニル）ビニル］−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン（８３０ｍｇ）のＤＭＦ（２５ｍｌ）溶液に１０％パラジウム−炭素（８００ｍｇ）を加えた後、水素ガス（１気圧）雰囲気下室温にて４０時間攪拌した。触媒を濾別した後、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；クロロホルム：メタノール＝２０：１）で精製し、４Ｍ塩化水素−酢酸エチル（１ｍｌ）を加え、析出した沈殿物を酢酸エチルで洗浄し、６−アゼパン−１−イル−３−［２−（２−メトキシフェニル）エチル］−７，８−ジヒドロ−１，２，４−トリアゾロ［４，３−ｂ］ピリダジン・塩酸塩（７４ｍｇ）を無色結晶として得た。
【００５７】
実施例１と同様に処理し、所望により４Ｍ塩化水素−酢酸エチルを用いた常法の造塩反応に付して、後記表７〜１７に示される実施例２９〜１６９及び表２０に示される実施例２０１〜２０９の化合物を得た。また、実施例２と同様にして表１７に示される実施例１７０の化合物を、実施例３と同様にして実施例１７１の化合物を、実施例４と同様にして実施例１７２及び１７３の化合物を、実施例５と同様にして実施例１７４及び１７５の化合物を、実施例６と同様にして実施例１７６の化合物を、実施例９と同様にして表１８に示される実施例１７７〜１７９の化合物を、実施例１３と同様にして実施例１８０及び１８１の化合物を、実施例１６と同様にして実施例１８２の化合物を、実施例１８と同様にして実施例１８３〜１８５の化合物を、実施例１９と同様にして表１８〜１９に示される実施例１８６〜１９７の化合物を、実施例２５と同様にして表１９に示される実施例１９８の化合物を、及び実施例２６と同様にして実施例１９９〜２００の化合物を、それぞれ得た。
【００５８】
後記表１〜５に参考例化合物の構造式と物理化学的性状を、表６〜２０に実施例化合物の構造式と物理化学的性状をそれぞれ示す。また、表２１において、それぞれＮｏ．１〜２０に示すＲ^１基を有する式（Ｉ−１）〜（Ｉ−４）で示される化合物は，適当な原料化合物を用いて、前記実施例若しくは製造法に記載の方法とほぼ同様にして，又は，それらに当業者に自明の若干の変法を適用して，容易に製造される。
表中の略号は、Ｒｅｘ：参考例番号；　Ｅｘ：実施例番号；　Ｓｔｒ：構造式；　Ｄａｔ：物理化学的性状（Ｆ：ＦＡＢ−ＭＳ　（Ｍ＋Ｈ）^＋；　Ｍ：融点［℃］；　（ｄ）：分解；　Ｎ１：ＮＭＲ（ＤＭＳＯ−ｄ_６，ＴＭＳ内部標準）の特徴的ピークδｐｐｍ）；Ｓａｌ：塩（　空欄：フリー体；ＨＣｌ：塩酸塩；　２ＨＣｌ：二塩酸塩）；　Ｍｅ：メチル；　Ｅｔ：エチル；及び　Ａｃ：アセチルを、それぞれ示す。
【００５９】
【表１】

【００６０】
【表２】

【００６１】
【表３】

【００６２】
【表４】

【００６３】
【表５】

【００６４】
【表６】

【００６５】
【表７】

【００６６】
【表８】

【００６７】
【表９】

【００６８】
【表１０】

【００６９】
【表１１】

【００７０】
【表１２】

【００７１】
【表１３】

【００７２】
【表１４】

【００７３】
【表１５】

【００７４】
【表１６】

【００７５】
【表１７】

【００７６】
【表１８】

【００７７】
【表１９】

【００７８】
【表２０】

【００７９】
【表２１】

【図面の簡単な説明】
【図１】試験例２における本発明化合物投与群並びに対照群の類骨幅を示す。
【図２】試験例２における本発明化合物投与群並びに対照群の石灰化速度を示す。[0001]
[Industrial applications]
The present invention relates to a nitrogen-containing heterocyclic compound having a function of promoting bone formation in osteoblasts or a pharmaceutically acceptable salt thereof.
[0002]
[Prior art]
In normal bone metabolism, bone resorption by osteoclasts and bone formation by osteoblasts are in equilibrium, and homeostasis is maintained. If the balance between bone resorption and bone formation is disrupted, it is considered to be a metabolic bone disease. The diseases include osteoporosis, fibrous osteomyelitis (hyperparathyroidism), osteomalacia, and Paget's disease which affects systemic bone metabolic parameters. In particular, osteoporosis is common in postmenopausal women and the elderly. Symptoms include pain such as lower back pain and bone fractures. Fractures in the elderly are particularly severe because they cause general weakness and dementia. For the treatment and prevention of such bone diseases, calcium preparations, active vitamin D₃Preparations, calcitonin preparations, estrogen preparations and the like are used.
However, although many of these therapeutic agents have been reported to have an effect of suppressing bone resorption, none of them has a clear effect of promoting bone formation. In particular, it has been reported that senile osteoporosis is mainly caused by a decrease in bone formation ability due to a decrease in bone turnover (New @ Eng. @ J. @ Med. @ 314, @ P1976, @ (1986)), and promotes bone formation. There is a long-awaited need for drugs to be used.
[0003]
Recently, benzothiepine derivatives having alkaline phosphatase-inducing activity (for example, see Patent Document 1) and N-quinolylanthranilic acid derivatives (for example, see Patent Document 2) have been reported to promote bone formation and treat metabolic bone diseases. Has been reported to be useful. However, its clinical utility is unknown.
[0004]
On the other hand, there are the following reports on triazolopyridazine derivatives (the symbols in the text indicate the symbols in the general formula (I) of the present invention described later). However, these literatures and patents do not disclose or suggest a bone formation promoting action.
(1) X¹, X²And Y is N, and Ra and Rb are united with adjacent N atoms to form piperidino;³And R⁴Is a compound in which both H and E are a single bond,²Is an antimicrobial compound in which is piperidino (see Patent Document 3); R²Of a compound in which is unsubstituted phenyl (see Non-Patent Document 1);²Is p- (trifluoromethyl) phenyl or p-chlorophenyl (see Non-Patent Document 2);²Are compounds which are o-nitrophenyl (see Non-Patent Document 3).
(2) X¹, X²And Y is N, and Ra and Rb are united with adjacent N atoms to form piperidino;³Is H, R⁴Is methyl, E is a single bond, and R²Are unsubstituted phenyl, m-methylphenyl, p-chlorophenyl, m-methoxyphenyl or p-nitrophenyl, and have disclosed triazolopyridazine derivatives having a bronchodilator effect (see Patent Documents 4 and 5).
(3) X¹, X²And Y are N, and Ra and Rb are united with an adjacent N atom to form 4-methyl-1-piperazinyl; E is a single bond;²Which is unsubstituted phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl, has a bronchodilator triazolopyridazine derivative. (See Patent Documents 4 and 5).
[0005]
(4) X¹, X²And Y is N, R²Is an imidazolyl which may have a substituent (see Patent Documents 6, 7 and 8);²Are 5-nitro-2-furyl or 5-nitro-2-thienyl (see Patent Documents 9, 10 and 11).
(5) X¹, X²And Y are N, and Ra and Rb are combined with an adjacent N atom to form an optionally substituted 1-pyrazolyl, E is a single bond, and R is²Is a compound wherein is an unsubstituted phenyl (see Non-Patent Documents 4 and 5);²Is a morpholino (see Non-Patent Document 6).
(6) X¹, X²And Y is N, Ra is H, Rb is cyclopropyl, E is a single bond, and R²Is a p- (trifluoromethyl) phenyl compound (see Non-Patent Document 7).
(7) X¹, X²And Y is N, Ra is methyl, Rb is 2-hydroxy-propyl, E is a single bond, and R²Is a compound having a hypertensive action, which is 3-pyridyl (see Non-Patent Document 8).
[0006]
Also, R¹And -ER²Is a benzodiazepine receptor ligand (see Non-Patent Documents 9 and 10); a compound having a hypertensive action and a bactericidal action (see Non-Patent Document 11); It has been reported as a drug (see Non-Patent Document 12 and Patent Document 12). There are also reports of the synthesis of compounds of this type (see, for example, Non-Patent Documents 13, 14, 1 5 and 16). R¹Is an unsubstituted or substituted phenyl group and -ER²Has been reported for the synthesis or antihypertensive action of a triazolopyridazine derivative having a pyridyl group が (see, for example, Non-Patent Documents 17 and 18). However, these documents do not disclose a bone formation promoting effect. Also, -ER²However, there is no disclosure of a triazolopyridazine derivative which is a phenyl having a substituent at the m-position or a 2-pyridyl group having a substituent at the 6-position.
[0007]
[Patent Document 1] JP-A-8-231569
[Patent Document 2] Japanese Patent Application Laid-Open No. 9-188665
[Patent Document 3] US Pat. No. 3,957,766
[Non-Patent Document 1] Tetrahedron, {22 (7), {2073-9} (1966)
[Non-patent Document 2] CAS Registry File RN = 289651-67-8 and 202820-26-6
[Non-patent document 3] Reagent catalog (SPECCS, The Netherlands) Refcode: AG-690 / 3073051
[Patent Document 4] German Patent 2,444,322
[Patent Document 5] Japanese Patent Application Laid-Open No. 50-58092
[Patent Document 6] German Published Patent Application No. 2,261,693
[Patent Document 7] German Published Patent Application No. 2,254,873
[Patent Document 8] German Published Patent Application No. 2,215,999
[Patent Document 9] German Published Patent Application No. 2,161,586
[Patent Document 10] German Patent Publication No. 2,161,587
[Patent Document 11] German Published Patent Application No. 2,113,438
[Non-Patent Document 4] Tetrahedron, $ 55 (1), 271-278, (1999)
[Non-Patent Document 5] {Heterocycl. {Chem. $ 35 (6), 1281-4, (1998)
[Non-Patent Document 6] CAS \ Registry \ File \ RN = 325706-90-9
[Non-Patent Document 7] CAS \ Registry \ File \ RN = 289651-68-9
[Non-Patent Document 8] Farmaco. {Ed. {Sci. , $ 34 (4), $ 299-310, $ (1979)
[Non-Patent Document 9] Acta. {Pol. {Pharm. $ 56 (1), $ 61-68, $ (1999)
[Non-Patent Document 10] Bioorg. {Med. {Chem. , 2 (8), 773-9, (1994)
[Non-Patent Document 11] Rev. {Med. -Chir. $ 81 (3), $ 469-74, $ 1977
[Non-Patent Document 12] {Med. {Chem. , 24 (5), 592-600, (1981)
[Patent Document 12] JP-A-59-184179
[Non-Patent Document 13] Egypt. {J. {Chem. , $ 43 (1), $ 17-29, $ (2000)
[Non-Patent Document 14] {Heterocycle. {Chem. $ 22 (4), $ 1045-8, $ (1985)
[Non-Patent Document 15] Indian @ J. {Chem. {Sect. B, $ 16B (2), $ 163-5, $ (1978)
[Non-Patent Document 16] Rev. {Roumaine} Chim. , $ 10 (7), $ 641-7, $ (1965)
[Non-Patent Document 17] Chemical Abstract CA61: 3103b
[Non-Patent Document 18] Chemical Abstract CA52: 18424f
[0008]
[Problems to be solved by the invention]
In order to reduce pain such as low back pain and fracture risk in metabolic bone diseases such as osteoporosis, it is necessary to increase bone mass and strength, and bone formation by osteoblasts, which is considered to be more effective There is a strong demand for the development of clinically useful bone formation promoters that have the effect of promoting bone marrow.
[0009]
[Means for Solving the Problems]
The present inventors have conducted intensive studies for the purpose of developing a therapeutic agent having a bone formation promoting action by promoting the function of osteoblasts. As a result, the following nitrogen-containing heterocyclic compound showed strong bone formation by osteoblasts. The present inventors have found that the compound has a promoting effect and can be an excellent preventive or therapeutic agent for metabolic bone disease, and completed the present invention.
[0010]
That is, the present invention relates to a nitrogen-containing heterocyclic compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
Embedded image

(The symbols in the formula have the following meanings.
X¹And X²: Same or different, N or CR⁵, At least one of which is N,
Y: N or X¹And X²When both are N, Y is CR⁶May be
Dotted line: single bond or double bond,
R¹: -NRaRb, provided that the group -ER²Is phenyl having a substituent at the m-position or 2-pyridyl having a substituent at the 6-position,¹Is an aryl which may have a substituent, a cycloalkyl which may have a substituent, a cycloalkenyl which may have a substituent, -O- (which may have a substituent Aryl), -S- (aryl which may have a substituent), -OC_1-2Alkylene- (aryl which may have a substituent), -OC_1-2Alkylene- (4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have a substituent) or -OC_1-2Alkylene-OR ',
Ra and Rb: identical or different, H; CO-lower alkyl; SO₂-Lower alkyl; cycloalkyl optionally having substituent (s); aryl optionally having substituent (s); or cycloalkyl optionally having substituent (s), optionally having substituent (s) Aryl, optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, CO-lower alkyl, SO₂Lower alkyl, OR ', SR', NR'R ", halogen, NO₂, CN, and lower alkyl optionally having 1 to 3 substituents selected from the group consisting of COOR '; provided that at least one of Ra and Rb represents a group other than H;
Alternatively, Ra and Rb are combined with an adjacent N atom to form a 4- to 8-membered saturated or unsaturated heterocyclic ring containing 1 to 2 N atoms as a heteroatom, wherein the heterocyclic ring is a benzene ring or May be condensed with a cycloalkyl ring, may have a bridge or may form a spiro ring, further, the hetero ring may have 1 to 5 substituents,
E: single bond, C_1-3Alkylene, vinylene (-C = C-), ethynylene (-C≡C-), CO, NR⁷, CH₂-J, CONR⁸Or NR⁹CO,
J: O, S, NR¹⁰, CO, SO or SO₂,
R²: Aryl which may have a substituent, heteroaryl which may have a substituent, cycloalkyl which may have a substituent, cycloalkenyl which may have a substituent, substituent A 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring, -OR 'or -P (= O) (OR') which may have₂
R³~ R¹⁰, R 'and R ": identical or different, H or lower alkyl
[0011]
However, the following compounds are excluded.
(1) X¹, X²And Y is N, and Ra and Rb are united with adjacent N atoms to form piperidino;³And R⁴Are both H and E are a single bond, and R²Is piperidino, unsubstituted phenyl, p- (trifluoromethyl) phenyl, p-chlorophenyl or o-nitrophenyl,
(2) X¹, X²And Y is N, and Ra and Rb are united with adjacent N atoms to form piperidino;³Is H, R⁴Is methyl, E is a single bond, and R²Is an unsubstituted phenyl, m-methylphenyl, p-chlorophenyl, m-methoxyphenyl or p-nitrophenyl,
(3) X¹, X²And Y are N, and Ra and Rb are united with an adjacent N atom to form 4-methyl-1-piperazinyl; E is a single bond;²Is unsubstituted phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl,
(4) X¹, X²And Y is N, R²Is an imidazolyl, 5-nitro-2-furyl or 5-nitro-2-thienyl optionally having substituent (s),
(5) X¹, X²And Y are N, and Ra and Rb are combined with an adjacent N atom to form an optionally substituted 1-pyrazolyl, E is a single bond, and R is²Is an unsubstituted phenyl or morpholino,
(6) X¹, X²And Y is N, Ra is H, Rb is cyclopropyl, E is a single bond, and R²Is p- (trifluoromethyl) phenyl, and
(7) X¹, X²And Y is N, Ra is methyl, Rb is 2-hydroxy-propyl, E is a single bond, and R²Is 3-pyridyl. The same applies hereinafter. )
[0012]
The present application also discloses an invention relating to a medicament containing the nitrogen-containing heterocyclic compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, particularly an osteogenesis promoter.
[0013]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
As used herein, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. As the "lower alkyl", a methyl, ethyl and propyl group are particularly preferred. In the present specification, “lower alkyl” is abbreviated as “Alk”. "C_1-2"Alkylene" is preferably methylene and ethylene.
"Aryl" is preferably C_6-14It is a monocyclic to tricyclic aryl group. More preferred are phenyl and naphthyl groups, and even more preferred are phenyl groups. Also, the phenyl group has C_5-8The cycloalkyl ring may be fused to form, for example, an indanyl or tetrahydronaphthyl group. "Cycloalkyl" is preferably C_3-14It is a cycloalkyl group and may have a bridge. More preferably C_3-10A cycloalkyl group, more preferably a cyclopentyl, cyclohexyl and cycloheptyl group. “Cycloalkenyl” is a group having one or two double bonds in the above “cycloalkyl” ring.
“4- to 8-membered monocyclic saturated or partially unsaturated heterocycle” is a 4- to 8-membered monocyclic saturated heterocycle containing 1 to 4 heteroatoms selected from N, S, and O, And may partially have an unsaturated bond. Preferred are tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidyl, 1,2,3,6-tetrahydropyridyl, homopiperidinyl, piperazinyl, homopiperazinyl, quinuclidinyl and morpholinyl groups.
[0014]
As the “heteroaryl”, a 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, S and O, and a benzene ring or a 5- or 6-membered monocyclic heteroaryl A fused bicyclic or tricyclic heteroaryl group, which may be partially saturated. Here, the 5- or 6-membered monocyclic heteroaryl includes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl groups Preferably, the bicyclic or tricyclic heteroaryl includes benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxaziazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl , Quinoxalinyl, benzodioxolyl, pyrazinopyridyl, triazolopyridyl, naphthyridinyl and imidazo Lysyl group is preferred. Examples of the partially saturated heteroaryl include a 1,2,3,4-tetrahydroquinolyl group. R²More preferred groups as heteroaryl in are pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, quinolyl, benzofuranyl, benzothienyl, indolyl, imidazopyridyl and naphthyridinyl groups, particularly preferably pyridyl group.
[0015]
"Optionally substituted aryl" and "optionally substituted heteroaryl", "optionally substituted cycloalkyl", "optionally substituted As the substituents in the “good cycloalkenyl” and the “optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring”, preferably the same or different selected from the following group B 1 to 5 substituents, more preferably Alk, halogeno Alk, halogen, NR′R ″, NO₂, CN, OR ', -O-halogenoAlk, SR', COOR ', CONR'R ", SO₂Alk, a 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, a group selected from phenyl and phenoxy, particularly preferably halogen, OAlk and SAlk.
Group B: Alk optionally having 1 to 4 substituents selected from Group E, halogen, NR'R ", NR'CO-Alk, NO₂, CN, OR ', -O- (Alk having 1-4 substituents selected from group E), SR', -S-halogenoAlk, -O-COAlk, COOR ', COR', CONR'R ”, SOAlk, SO₂Alk, SO₂NR'R ", P (= O) (OR ')₂, -O-CH₂-O-, -O- (CH₂)₂-O-, aryl optionally having 1 to 4 substituents selected from group D, heteroaryl optionally having 1 to 4 substituents selected from group D, -O- (Aryl which may have 1 to 4 substituent (s) selected from Group D), 4 to 8 membered monocyclic saturated which may have 1 to 4 substituent (s) selected from Group D Or a partially unsaturated heterocycle, cycloalkyl and -O-cycloalkyl. Here, R ′ and R ″ are as described above; “Group D” is Alk, halogen, halogenoAlk, NR′R ″, NO₂, CN, OR ′, and SR ′; “Group E” has 1 to 4 substituents selected from halogen, NR′R ″, CN, COOR ′, OR ′, SR ′, and D; A 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, an aryl optionally having 1 to 4 substituents selected from Group D, and 1 to 4 substituents selected from Group D "Halogen" is I, Br, F and Cl; and "halogeno Alk" is lower alkyl substituted with one or more halogen atoms (particularly preferably₃) Are shown.
[0016]
The “4- to 8-membered saturated or unsaturated heterocyclic ring containing one or two N atoms as a hetero atom” formed by Ra and Rb integrally with an adjacent N atom includes one N atom as a ring atom. A 5- or 7-membered monocyclic aromatic heterocycle or a 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic group. The hetero ring is a benzene ring or C_5-8It may form a condensed ring with a cycloalkyl ring, may have a bridge, or may form a spiro ring. Preferably, pyrrolyl, imidazolyl, pyrazolyl, indolyl, isoindolyl, pyrrolidinyl, piperidyl, homopiperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, homopiperazinyl, perhydroazosinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl , 1,2-dihydropyridyl, tetrahydropyridazinyl, tetrahydropyrazinyl, 1,4,5,6-tetrahydropyrimidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,2 3,4-tetrahydroisoquinolyl, 3-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.2.1] octyl, 3-azabicyclo [3.2.2] nonyl, 3-azabicyclo [3 3.3.1] Nyl, 7-azabicyclo [2.2.1] heptyl, isoquinuclidinyl, 3-azabicyclo [3.3.2] decanyl, 3-azaspiro [5.5] undecanyl, 2-azaspiro [4.5] Decanyl, 2-azaspiro [4.4] nonyl, 8-azaspiro [4.5] decanyl and the like. More preferably, it is a 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have a bridge, and among them, pyrrolidinyl, piperidyl, homopiridinyl, perhydroazosinyl, 1,2,3 , 6-Tetrahydropyridyl, 3-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.2.1] octyl, 3-azabicyclo [3.2.2] nonyl and 3-azabicyclo [3.3. 1] A nonyl group is preferred, and a piperidyl group is particularly preferred.
Further, the hetero ring may have a substituent, and the substituent is preferably 1 to 5 substituents selected from the group B. More preferably, halogen, NR′R ″, CN, (Alk optionally substituted with COOR ′, OR ′ or phenyl), O— (Alk substituted with COOR ′ or OR ′), COOR ′, OR 1 to 5 substituents selected from ', SR', CONR'R "and phenyl, particularly preferably 1 to 2 substituents selected from Alk, halogen, OR 'and COOR'.
[0017]
Hereinafter, preferred compounds in the compound (I) of the present invention will be described.
(1) R¹Is -NRaRb.
(2) a compound in which the dotted line is a double bond,
(3) R³And R⁴Are both H,
(4) X¹Is N, X²Is N or a compound wherein CH and Y are N, more preferably X¹, X²And Y is all N.
(5) R¹May be condensed with a benzene ring or a cycloalkyl ring as —NRaRb, may have a bridge, or may form a spiro ring, and has 1 to 5 substituents selected from Group B Forms a 4- to 8-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 N atoms as a ring heteroatom; E is a single bond, C_1-3Alkylene, vinylene, ethinylene, NHCO, CH₂NH, CH₂O or CH₂S; R²Is an aryl optionally having 1 to 5 substituents selected from Group B or a heteroaryl optionally having 1 to 5 substituents selected from Group B.
(6) E is a single bond, C_1-3Alkylene, vinylene or ethynylene; R²Is Alk, halogeno Alk, halogen, NR'R ", NO₂, CN, OR ', -O-halogenoAlk, SR', COOR ', CONR'R ", SO₂Alk, a 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, aryl having 1 to 5 substituents selected from the group selected from phenyl and phenoxy, or Alk, halogeno Alk, halogen, NR'R ", NO₂, CN, OR ', -O-halogenoAlk, SR', COOR ', CONR'R ", SO₂Alk, a compound that is a 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, a heteroaryl having 1 to 5 substituents selected from the group selected from phenyl and phenoxy.
(7) R¹May have one N atom as a ring heteroatom as -NRaRb and may have a bridge, and have 1 to 2 substituents selected from Alk, halogen, OR 'and COOR'. R is a 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring; E is a single bond;²Is phenyl having a substituent selected from the group consisting of halogen, OAlk and SAlk at the m-position, and pyridyl having a substituent selected from halogen, OAlk and SAlk at the 6-position.
[0018]
Particularly preferred compounds in the present invention are the following nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof.
6-azocan-1-yl-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azepan-1-yl-3- (6- Bromopyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 3- (3-methoxyphenyl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine, 3- (3-bromophenyl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azepan-1- Yl-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6- (4-fluoropiperidin-1-yl) -3- (6-methoxy) Pyridin-2-yl) -1,2,4-triazolo [4,3-b] Ridazine, 6- (3-azabicyclo [3.2.1] octan-3-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine , 6- (4,4-difluoropiperidin-1-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6- (3 3-difluoropiperidin-1-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azocan-1-yl-3- ( 6-bromopyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine and 6- (8-azabicyclo [3.2.1] octan-8-yl) -3- ( 6-bromopyridin-2-yl) -1,2,4-triazolo [4 3-b] pyridazine.
[0019]
Depending on the type of the substituent of the present invention, a geometric isomer or a tautomer may exist, but the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and optical isomers based on this may exist. The present invention embraces all of these optical isomer mixtures and isolated ones.
[0020]
The compound (I) of the present invention may form an acid addition salt or a salt with a base depending on the type of the substituent. Such salts are pharmaceutically acceptable salts, preferably, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, and oxalic acid. Acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, acid addition salts with organic acids such as glutamic acid, sodium, potassium, Examples thereof include inorganic bases containing metals such as magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts.
Furthermore, the present invention also includes various hydrates, solvates and polymorphic substances of the compound (I) of the present invention and salts thereof.
[0021]
(Manufacturing method)
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents. At that time, depending on the type of the functional group, if it is effective from the viewpoint of production technology, it is preferable to replace the functional group with a suitable protecting group at the stage of the raw material or intermediate, that is, a group which can be easily converted to the functional group. There is. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of such a protective group are described in "Protective Groups in Organic Synthesis" by Green and Wuts, 2nd edition. And these may be appropriately used depending on the reaction conditions.
[0022]
Hereinafter, a typical production method of the compound of the present invention will be described.
First manufacturing method
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(In the formula, L represents a conventional leaving group such as a halogen atom or an organic sulfonate. The same applies hereinafter.)
The compound (Ia) of the present invention can be obtained by converting an N-alkylated compound in a conventional manner, for example, an amine derivative (III) and a compound (II) having a common leaving group such as a halogen atom or an organic sulfonate with potassium carbonate, triethylamine. , In the presence or absence of a base such as sodium hydride, in an inert solvent such as N, N-dimethylformamide (DMF), toluene, tetrahydrofuran (THF), acetonitrile, or without a solvent, under cooling. The reaction can be carried out under reflux.
[0023]
Second manufacturing method
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(Wherein, Z represents O or S, Rc represents an aryl which may have a substituent, -C_{1- 2}Alkylene- (aryl which may have a substituent), -C_1-2Alkylene- (4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring which may have a substituent) or -C_1-2And alkylene-OR '. )
The compound (Ib) of the present invention can be obtained by converting a compound (II) having a common leaving group such as a halogen atom or an organic sulfonate with a compound (II) having a conventional leaving group such as an alcohol or a thiol derivative (IV) by a conventional method. Reaction in the presence or absence of a base such as potassium, tert-butylamine, and sodium hydride in an inert solvent such as DMF, toluene, THF, acetonitrile, or without a solvent under cooling to reflux. Can be done by
[0024]
Third manufacturing method
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(In the formula, Ar represents aryl which may have a substituent, cycloalkyl which may have a substituent, or cycloalkenyl which may have a substituent.)
The compound (Ic) of the present invention is obtained by converting a hydrazine derivative (VI) with a compound (V) having a common leaving group such as a halogen atom or an organic sulfonate in the presence of an acid such as acetic acid, p-toluenesulfonic acid and hydrochloric acid. The reaction can be carried out in a solvent such as methanol, ethanol, ethylene glycol or the like in the absence or absence of the solvent or without a solvent. This reaction can be carried out at room temperature to under reflux with heating.
Other manufacturing methods
The compound obtained in the first production method is further subjected to a conventional substituent modification reaction, for example, a reduction reaction of a nitro group to an amino group, amidation, sulfonamidation, N-alkylation, esterification, esterification. The compound of the present invention having a desired substituent can be obtained by subjecting it to hydrolysis, etherification of a hydroxyl group, sulfonation of a thioether, halogenation, olefination and the like. These reactions can be easily carried out, for example, according to the method described in ORGANIC / FUNCTIONAL / GROUP / PREPARATIONS / Second / Edition (by Sandler, @Karo).
[0025]
(Method for producing raw material compounds)
Manufacturing method a
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The starting compound (IIa) of the present application can be produced by subjecting a hydrazine compound (IV) and a carboxylic acid compound (V) to a dehydration condensation reaction to form a hydrazide compound (VI), and then cyclizing the compound.
[0026]
The dehydration-condensation reaction in the first step can be performed by a conventional method. For example, a free carboxylic acid and a condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSCD) or 1,1′- Using a carboxylic acid activator such as carbonyldiimidazole, or a reactive derivative of carboxylic acid (for example, acid halide such as acid chloride, acid bromide; acid azide; methanol, ethanol, benzyl alcohol, Active esters that can be prepared using phenol, N-hydroxysuccinimide, etc .; symmetric acid anhydrides; mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, etc.).
The reaction is carried out in an organic solvent inert to the reaction, for example, pyridine, THF, methylene chloride, DMF, acetonitrile, etc., using an equimolar amount or one of them in excess. The reaction temperature is appropriately selected depending on the type of the reactive derivative. Depending on the type of the reactive derivative, it may be advantageous to add a base such as 4-dimethylaminopyridine to promote the reaction.
The cyclization reaction in the second step is performed by reacting in the presence or absence of an acid such as acetic acid, p-toluenesulfonic acid, or hydrochloric acid in a solvent such as xylene or ethylene glycol, or without a solvent. Can be. This reaction can be carried out at room temperature to under reflux with heating.
[0027]
Manufacturing method b
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The starting compound (XIV) of the present application is obtained by reacting the compound (X) with the compound (XI) in an acidic solvent such as acetic acid to give a compound (XII), to which phosphorus oxychloride or the like is added and subjected to a cyclization reaction to give the compound (XIII ) And catalytic reduction of a nitro group in an alcohol solvent using palladium carbon as a catalyst. Any of the reactions can be carried out by a conventional method at room temperature or under reflux.
[0028]
Manufacturing method c
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The starting compound (IIb) of the present application is obtained by reacting the compound (XV) with hydrazine monohydrate in an alcohol solvent to obtain the compound (XVI), and then subjecting the compound (XVI) to an oxidation reaction using bromine in an acidic solvent such as acetic acid. (XVII) can be produced by adding this compound to phosphorus oxychloride and cyclizing the compound. The reaction can be carried out in any ordinary manner from room temperature to under reflux with heating.
[0029]
Manufacturing method d
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The starting compound (IIc) of the present invention is obtained by reacting the compound (XVIII) with the compound (XIX) in a solvent inert to a reaction such as 1,4-dioxane in the presence of a base such as triethylamine to give the compound (XX). Thereafter, an oxidizing agent such as a sulfur trioxide pyridine complex or the like is reacted in a solvent such as methylene chloride or dimethyl sulfoxide (DMSO) in the presence of a base such as triethylamine to obtain a compound (XXI). And cyclization with an acid such as trifluoroacetic anhydride. All of the reactions can be carried out by a conventional method under ice cooling or heating to reflux.
[0030]
Manufacturing method e
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The starting compound (IId) of the present application can be produced by reacting the compound (XXII) with the compound (XXIII) in a solvent inert to the reaction such as DMF at room temperature or under heating to reflux to effect cyclization. .
[0031]
Manufacturing method f
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The starting compound (IIe) of the present application is obtained by condensing the compound (VII) and the isocyanate compound (XXIV) in a solvent inert to the reaction such as acetonitrile to obtain the compound (XXV), and then reacting the compound (XXV) in the presence of a base such as triethylamine. , 1,2-dibromo-1,1,2,2-tetrachloroethane and triphenylphosphine to be cyclized. The reaction can be appropriately carried out at room temperature or under reflux with heating according to a conventional method.
[0032]
The reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt, a hydrate or various solvates. The salt can be produced by subjecting the salt to a usual salt formation reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. The optical isomer can also be synthesized from an appropriate optically active starting compound.
[0033]
【The invention's effect】
The compound of the present invention has an effect of promoting bone formation by osteoblasts and promoting bone formation, and prevents or treats a metabolic bone disease associated with a decrease in bone formation ability as compared to bone resorption ability. Useful for Such metabolic bone diseases include osteoporosis, fibrous osteopathy (hyperparathyroidism), osteomalacia, and Paget's disease, which further affects systemic bone metabolic parameters. Particularly, it is useful for senile osteoporosis in which bone formation ability is reduced.
Further, the bone formation promoting agent of the present invention can be applied to the promotion of the healing of bone diseases such as bone fractures, bone defects and osteoarthritis in the orthopedic field, the treatment of periodontal disease and the stability of artificial dental roots in the dental field. Can be expected.
[0034]
Osteoblast phenotypes include alkaline phosphatase (ALP) activity, production of bone matrix proteins (collagen, osteocalcin, osteonectin, osteopontin, etc.), active vitamin D₃Receptors, parathyroid hormone receptors, estrogen receptors and androgen receptors (Molecular Medicine, Vol. 30, No. 10, 1232 (1993)). ALP is increased from the early stage of osteoblast function expression (Journal of Cellular Physiology, Vol. 143, 420 (1990)). The role of ALP on bone formation by osteoblasts is believed to be to increase the phosphate ion concentration locally at the bone formation site and to decompose pyrophosphate, which is a calcification inhibitor (Cell Engineering, Vol. 13, 12, No. 1062 (1994)). In addition, it has been shown that calcification occurs when a substance obtained by covalently bonding ALP and a collagen sheet is subcutaneously transplanted into rats (J. Clin. Invest., 89, 1974 (1992)). Therefore, an increase in ALP activity of osteoblasts can be evaluated as an index for promoting bone formation.
[0035]
Hereinafter, tests and results for proving the pharmacological action of the compound of the present invention will be described.
Test Example 1: Alkaline phosphatase in mouse osteoblast cell line (ALP) Activity measurement
A mouse-derived osteoblast cell line MC3T3-E1 was seeded at a concentration of 3000 cells / well in a 96-well plate in an α-minimum essential medium (MEM: minimum essential medium) containing 5% fetal bovine serum (FBS). Cultured for 4-6 hours. A test compound dissolved in dimethylsulfoxide (DMSO) was added to the adhered cells (DMSO final concentration: 0.5%), and the cells were further cultured for 3 days. After washing the cells with phosphate buffered saline, the substrate was added and incubated at 37 ° C. for 10-15 minutes. The reaction was stopped by adding 0.5 M sodium hydroxide, the absorbance at 405 nm (reference wavelength 492 nm) was measured, and the ALP activity was calculated as a% value with respect to the control group as 100%. In addition, the said measuring method was performed with reference to the method of Lowry et al. (Journal of Biological Chemistry, volume 207, page 19 (1954)).
Embodiments 3, 9, 18, 30, 33, 34, 39, 40, 47, 48, 51, 57, 58, 62, 65, 66, 71, 76, 83, 103, 108, 115, 118 of the present invention. , 119, 126, 131, 132, 133, 134, 143, 144, 145, 146, 147, 155, 162, 169, 179, 183, 184, 185, 201, 204, 207 and 209 have a 300 nM compound. It had more than 300% ALP activity compared to the control group at the concentration.
[0036]
Test Example 2: Osteogenesis promotion test by local administration in rats
The compound (1, 10, or 100 μg) of Example 33 of the present invention was dispersed in 0.1 ml of mineral oil, and a 25-G needle was subcutaneously subcutaneously on the right side of a 10-week-old male Wistar II rat (n = 6) under ether anesthesia. The administration was performed once a day for 10 days using the attached 1 ml syringe. As a control, rats to which only 0.1 ml of mineral oil was administered once a day for 10 consecutive days were used. On the 11th day from the start of the administration, the drug was stopped. On the 18th day, the rats were sacrificed and the calvariae were removed. Prior to sacrifice, tetracycline (25 mg / kg) was administered subcutaneously on the back on the 10th day of administration and calcein (20 mg / kg) on the 16th day of administration, and bone labeling was performed. After fixing the removed calvaria with 70% ethanol, a section of the premaxillary transection was prepared according to a conventional method, and bone morphology was measured. FIGS. 1 and 2 show the osteoid width and the calcification rate of the compound of the present invention and the control group.
By administration of the compound of the present invention, significant increases in bone width and calcification rate were observed, and the excellent bone formation promoting activity of the compound of the present invention was confirmed.
[0037]
The medicament containing the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is one or more of the general formula (I) or a pharmaceutically acceptable salt thereof, It can be prepared by a commonly used method using pharmaceutical carriers, excipients, and other additives usually used for formulation. Oral administration by tablets, pills, capsules, granules, powders, liquids, inhalants, etc., or injections such as intravenous injections, intramuscular injections, suppository transdermal solutions, ointments, transdermal patches Any form of parenteral administration with an agent or the like may be used.
[0038]
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid. In a conventional manner, the composition may contain additives other than inert diluents, such as lubricants, such as magnesium stearate, disintegrants, such as calcium cellulose glycolate, stabilizers, glutamic acid or aspartic acid. A solubilizing agent may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or a film of a gastric or enteric substance.
[0039]
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water. , Ethanol. The composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.
Usually, in the case of oral administration, the daily dose is about 0.001 to 10 mg / kg, preferably 0.01 to 5 mg / kg per body weight, which is divided into single doses or 2 to 4 doses. Administration. When administered intravenously, the daily dose is suitably about 0.0001 to 1 mg / kg per body weight and is administered once a day or divided into a plurality of doses. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like.
[0040]
【Example】
Hereinafter, the present invention will be described in more detail based on examples. The compounds of the present invention are not limited to the compounds described in the following examples. The production method of the starting compound is shown in Reference Examples. The abbreviations in the text are Dat: physicochemical properties, F: FAB-MS (M + H)⁺And the other abbreviations are as described above.
[0041]
Reference Example 1: A mixture of (6-chloropyridazin-3-yl) hydrazine, 4-nitrobenzoic acid, WSCD hydrochloride, and THF was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the deposited precipitate was collected by filtration and washed with water and diethyl ether to obtain N '-(6-chloropyridazin-3-yl) -4-nitrobenzohydrazide. After acetic acid was added thereto and stirred at 110 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude crystals were washed with ethanol, and 6-chloro-3- (4-nitrophenyl) -1, 2,4-Triazolo [4,3-b] pyridazine was obtained. Dat (F: 276)
Reference Example 2: To a THF solution of (6-chloropyridazin-3-yl) hydrazine and triethylamine was added 3-cyanobenzoyl chloride under ice-cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, and the deposited precipitate was collected by filtration and washed with water and diethyl ether to obtain N '-(6-chloropyridazin-3-yl) -3-cyanobenzohydrazide. After acetic acid was added thereto and the mixture was stirred at 110 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure, and the obtained crude crystals were washed with ethanol, and 3- (6-chloro-1,2,4-triazolo [4 , 3-b] pyridazin-3-yl) benzonitrile. Dat (F: 256)
[0042]
Reference Example 3: A mixture of (6-chloropyridazin-3-yl) hydrazine, 3-dimethylaminobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the deposited precipitate was collected by filtration and washed with water and diisopropyl ether to obtain N '-(6-chloropyridazin-3-yl) -3-dimethylaminobenzohydrazide. Ethylene glycol was added thereto, and the mixture was stirred at 160 ° C. for 4 hours. After allowing to cool to room temperature, purification was conducted by a conventional method to obtain 6-chloro-3- (3-dimethylaminophenyl) -1,2,4-triazolo [4,3-b] pyridazine. Dat (F: 274)
Reference Example 4: After stirring a solution of 3-methoxyphenyl isocyanate and 3-chloro-6-hydrazinopyridazine in acetonitrile at room temperature for 30 minutes, 1,2-dibromo-1,1,2,2-tetrachloroethane was added. The mixture was further stirred at room temperature for 2 hours. Triethylamine and triphenylphosphine were added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 3 days. After that, the reaction solution was concentrated under reduced pressure and purified by a conventional method to give 6-chloro-N- (3-methoxyphenyl). -1,2,4-Triazolo [4,3-b] pyridazin-3-amine was obtained. Dat (F: 276)
Reference Example 5: A mixture of 3,6-dichloro-4-methylpyridazine, hydrazine monohydrate, triethylamine and 1,4-dioxane was stirred at 100 ° C. for 8 hours, and purified by a conventional method to obtain 3-chloro- A mixture of 6-hydrazino-4-methylpyridazine and 6-chloro-3-hydrazino-4-methylpyridazine was obtained. To this, 3-methoxybenzoic acid, WSCD hydrochloride and methylene chloride were added, and the mixture was stirred at room temperature for 5 hours and purified by a conventional method to give N '-(6-chloro-5-methylpyridazin-3-yl) -3. A mixture of -methoxybenzohydrazide and N '-(6-chloro-4-methylpyridazin-3-yl) -3-methoxybenzohydrazide was obtained. Acetic acid was added thereto, and the mixture was stirred at 100 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, and purified by a conventional method to give 6-chloro-3- (3-methoxyphenyl) -7-methyl-1,2. , 4-Triazolo [4,3-b] pyridazine was obtained. Dat (F: 275)
[0043]
Reference Example 6: After stirring a mixture of 2-chloro-5-nitropyridine, 3-methoxybenzohydrazide and acetic acid for 18 hours under heating and refluxing, the mixture was purified by a conventional method to give 3-methoxy-N ′-(5-nitro (Pyridin-2-yl) benzohydrazide was obtained. Phosphorus oxychloride was added thereto, and the mixture was stirred at 100 ° C. for 7 hours and purified by a conventional method to give 3- (3-methoxyphenyl) -6-nitro-1,2,4-triazolo [4,3-a Pyridine was obtained. Ethanol and 10% palladium-carbon were added thereto, and the mixture was stirred at room temperature and normal pressure for 5 hours under a hydrogen atmosphere, and then purified by a conventional method to give 3- (3-methoxyphenyl) -1,2,4-triazolo [4. , 3-a] pyridin-6-amine. Dat (F: 240)
Reference Example 7: A mixture of 2- (3-methoxyphenyl) -1,3-oxazol-5 (4H) -one, triethylamine, 4- (dimethylamino) pyridine and THF was added to a mixture of 4-chloro-4- under ice-cooling. A solution of ethyl oxobutyrate in THF was added, and the mixture was stirred at ice-cooling to room temperature for 2 hours, and then concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was stirred under heating and reflux for 3 hours, and then purified by a conventional method to obtain ethyl 5-[(3-methoxybenzoyl) amino] -4-oxopentanoate. Hydrazine monohydrate and ethanol were added thereto, and the mixture was stirred under heating and reflux for 1 hour and purified by a conventional method to give 3-methoxy-N-[(6-oxo-1,4,5,6-tetrahydropyridazine. -3-yl) methyl] benzamide was obtained. Acetic acid was added thereto, and bromine was gradually added dropwise. After stirring at 50 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by a conventional method to obtain 3-methoxy-N-[(6-oxo-1,6-dihydropyridazin-3-yl) methyl] benzamide. Phosphorus oxychloride was added thereto, and the mixture was stirred at 100 ° C. for 2 hours and purified by a conventional method to obtain 2-chloro-7- (3-methoxyphenyl) -imidazo [1,5-b] pyridazine. . Dat (F: 260)
Reference Example 8: 3'-Methoxyphenacyl bromide was added to a DMF solution of N '-(6-chloropyridazin-3-yl) -N, N-dimethylformamidine, and the mixture was stirred under heating and reflux for 3 hours. After the reaction solution was cooled to room temperature, it was purified by a conventional method to obtain (6-chloroimidazo [1,2-b] pyridazin-3-yl)-(3-methoxyphenyl) methanone. Dat (F: 288)
[0044]
Reference Example 9: A methanol solution of nitromethane and sodium methoxide was added to a methanol solution of 6-methoxypyridine-2-carbaldehyde, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with acetic acid and purified by a conventional method to obtain 1- (6-methoxypyridin-2-yl) -2-nitroethanol. This was dissolved in diethyl ether and added dropwise to a suspension of lithium aluminum hydride in diethyl ether at room temperature. After stirring at room temperature for 1 hour, purification was carried out by a conventional method to obtain 2-amino-1- (6-methoxypyridin-2-yl) ethanol. To this, 1,4-dioxane, triethylamine and 2,6-dichloropyridazine were added, and the mixture was stirred under heating and reflux for 21 hours, and then purified by a conventional method to give 2-[(6-chloropyridazin-3-yl) amino]. -1- (6-Methoxypyridin-2-yl) ethanol was obtained. This was dissolved in methylene chloride, DMSO, triethylamine, and sulfur trioxide pyridine complex were added thereto under ice cooling, and the mixture was stirred at room temperature for 2 hours, and purified by a conventional method to give 2-[(6-chloropyridazin-3-yl). Amino] -1- (6-methoxypyridin-2-yl) ethanone was obtained. To this, trifluoroacetic acid and trifluoroacetic anhydride were added, and after stirring at room temperature for 13 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by a conventional method to obtain 6-chloro-3- (6-methoxypyridin-2-yl) imidazo [1,2-b] pyridazine. Dat (F: 261)
In the same manner as in Reference Example 1, the compounds of Reference Examples 10 to 88 shown in Tables 1 to 4 described below, the compound of Reference Example 89 in the same manner as in Reference Example 8, the compound of Reference Example 90 in the same manner as in Reference Example 9, and 91 compounds were each obtained.
[0045]
Example 1 A mixture of 3- (6-chloro-1,2,4-triazolo [4,3-b] pyridazin-3-yl) benzonitrile (450 mg) and piperidine (5 ml) was heated at reflux for 2 hours. Stirred. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with chloroform. The extract was washed with a saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] benzonitrile (435 mg). Was obtained as pale yellow crystals.
Example 2: To a solution of 60% sodium hydride (30 mg) in DMF (5 ml) was added pyrazole (50 mg) under ice-cooling, and the mixture was stirred for 20 minutes, followed by 6-chloro-3- (6-methoxypyridine-2-yl). Yl) -1,2,4-triazolo [4,3-b] pyridazine (140 mg) was added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction solution, which was diluted with ethyl acetate. The organic layer was washed sequentially with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 3- (6-methoxypyridin-2-yl) -6- (1H-pyrazol-1-yl) -1,2,4-triazolo [4,3-b ] Pyridazine (39 mg) was obtained as pale yellow crystals.
Example 3 A solution of N-cyclopentyl-3- (3-methoxyphenyl) -1,2,4-triazolo [4,3-b] pyridazin-6-amine (300 mg) in DMF (5 ml) was added under ice cooling to a solution of 60. % Sodium hydride (44 mg) was added, and the mixture was stirred at ice-cooling to room temperature for 1 hour. Then, methyl iodide (68 μl) was added, and the mixture was further stirred for 2 hours. After water was added to the reaction mixture, it was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1), recrystallized from ethyl acetate, and N-cyclopentyl-3- (3-methoxyphenyl) -N-methyl- 1,2,4-Triazolo [4,3-b] pyridazin-6-amine (145 mg) was obtained as pale yellow crystals.
[0046]
Example 4: To a mixture of potassium hydroxide (98 mg) and DMSO (5 ml) was added 6-azepan-1-yl-3- (1H-indol-2-yl) -1,2,4-triazolo [4,3- b] Pyridazine (501 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl iodide (0.15 ml) was added, and the mixture was further stirred at room temperature for 2 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration, washed with a water-methanol mixed solvent, and then purified by silica gel column chromatography (eluent; chloroform: methanol = 99: 1). The obtained crude crystals were recrystallized from ethanol to give 6-azepan-1-yl-3- (1-methylindol-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (40 mg). ) Was obtained as colorless crystals.
Example 5: A mixture of 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] aniline (180 mg) and acetic anhydride (3 ml). Stirred at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure, and the obtained crude crystals are washed with diethyl ether to give 3 '-[6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b ] Pyridazin-3-yl] acetanilide (190 mg) was obtained as colorless crystals.
Example 6: 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo [4,3-b] pyridazine (670 mg), triethylamine (360 mg) and methylene chloride (15 ml) Methanesulfonyl chloride (320 mg) was added to the mixed solution, and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 3- (1-methanesulfonylpiperidin-3-yl) -6-piperidin-1-yl-1,2,4-triazolo [4,3-b] pyridazine ( 230 mg) as colorless crystals.
[0047]
Example 7: 6-chloro-3- (3-methoxyphenyl) -1,2,4-triazolo [4,3-b] pyridazine (880 mg), phenol (350 mg), potassium carbonate (700 mg) and DMF (10 ml) )) Was stirred at 80 ° C. for 10 hours. Water was added to the reaction solution, which was diluted with ethyl acetate. The organic layer was washed successively with water, 1 M aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 3- (3-methoxyphenyl) -6-phenoxy-1,2,4-triazolo [4,3-b] pyridazine (800 mg) as colorless crystals.
Example 8: To a solution of 2-piperidin-1-ylethanol (0.13 g) in DMF (5 ml) was added 60% sodium hydride (50 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Chloro-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (0.22 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 4M hydrogen chloride-1,4-dioxane solution (1 ml) was added to an ethanol solution (10 ml) of the obtained residue, and the mixture was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol-ethyl acetate to give 3- ( 6-Methoxypyridin-2-yl) -6- (2-piperidin-1-ylethoxy) -1,2,4-triazolo [4,3-b] pyridazine dihydrochloride (0.12 g) as colorless crystals. Obtained.
Example 9: 6-azocan-1-yl-3- (6-chloropyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (360 mg), sodium methoxide (570 mg) And a mixture of toluene (20 ml) was stirred with heating under reflux for 3 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were washed with diethyl ether, and 6-azocan-1-yl-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (290 mg) ) Was obtained as pale yellow crystals.
[0048]
Example 10: To a mixture of 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] phenol (300 mg) and DMF (5 ml), After adding 60% sodium hydride (49 mg) under ice-cooling and stirring for 30 minutes, ethyl iodide (0.10 ml) was added under ice-cooling and stirring was performed again for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1), recrystallized from ethanol, and 3- (3-ethoxyphenyl) -6- (piperidin-1-yl). -1,2,4-Triazolo [4,3-b] pyridazine (187 mg) was obtained as brown crystals.
Example 11: 6-chloro-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (0.22 g), tert-butylamine (2 ml), ethylene The mixture of glycol (2 ml) was stirred at 100 ° C. overnight. This was cooled to room temperature, and the precipitated solid was collected by filtration, washed successively with ethanol and diethyl ether, and dried to give 2-{[3- (6-methoxypyridin-2-yl) -1,2,2,3. 4-Triazolo [4,3-b] pyridazin-6-yl] oxyethanol (75 mg) was obtained as colorless crystals.
Example 12: 3- (3-nitrophenyl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine (560 mg), 10% palladium-carbon (60 mg). Ammonium formate (870 mg) was added to a mixture of ethanol and ethanol (40 ml) at room temperature, followed by stirring at 50 ° C. for 6 hours. After allowing to cool to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol-water (9: 1) to give 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine-3-. [Il] aniline (280 mg) was obtained as colorless crystals.
[0049]
Example 13: Methyl 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] benzoate (803 mg) and a 1 M aqueous sodium hydroxide solution ( 20 ml) of the mixture was stirred at 100 ° C. for 30 minutes. 1M hydrochloric acid (20 ml) was added to the reaction solution under ice cooling, and the precipitated solid was collected by filtration and washed with water. The obtained crude crystals were recrystallized from ethanol, and 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] benzoic acid (560 mg). Was obtained as colorless crystals.
Example 14: 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazin-3-yl] benzoic acid (430 mg), catalytic amounts of DMF and THF ( Oxalyl chloride (0.44 ml) was added to the mixed solution (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Then, ammonia gas was passed through the mixture under ice-cooling for 15 minutes. The reaction solution was concentrated under reduced pressure, chloroform-methanol (10: 1) was added to the obtained residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethanol to give 3- [6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine-3-. [L] benzamide (242 mg) was obtained as light brown crystals.
[0050]
Example 15: A mixture of 3-chloro-6-phenylpyridazine (2.29 g), 3-methoxybenzoylhydrazine (1.66 g) and acetic acid (20 ml) was stirred at 110 C for 1 day. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was neutralized with a saturated aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to give 3- (3-methoxyphenyl) -6-phenyl-1,2,4-triazolo [4,3-b] pyridazine (1.18 g) as colorless crystals. Was.
Example 16: To a solution of 3- [3- (methylsulfanyl) phenyl] -6-piperidin-1-yl-1,2,4-triazolo [4,3-b] pyridazine (550 mg) in methylene chloride (30 ml). At room temperature, 3-chloroperbenzoic acid (1.25 g) was added, and the mixture was stirred for 13 hours. Water was added to the reaction solution, which was diluted with methylene chloride. The organic layer was washed successively with water, 1 M aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent; chloroform: methanol = 98: 2), washed with ethanol, and 3- [3- (methylsulfonyl) phenyl] -6-piperidin-1-yl. -1,2,4-Triazolo [4,3-b] pyridazine (250 mg) was obtained as colorless crystals.
[0051]
Example 17: A mixture of concentrated sulfuric acid (1.5 ml) and water (3 ml) was cooled to -5 ° C and 4- (6-piperidin-1-yl-1,2,4-triazolo [4,3- b] Pyridazin-3-yl) -1,3-thiazol-2-amine (0.90 g), copper (II) sulfate (1.50 g) and sodium bromide (0.62 g) were sequentially added, and the mixture was added at 0 ° C. for 5 hours. After stirring for minutes, an aqueous solution (1.6 ml) of sodium nitrite (0.25 g) was added dropwise, and the mixture was stirred at room temperature overnight. Water, chloroform and 2-propanol were added to the reaction solution, and insolubles were removed by filtration. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1), and the obtained crude crystals were recrystallized from ethanol-diethyl ether to give 3- (2-bromo-1). , 3-Thiazol-4-yl) -6-piperidin-1-yl-1,2,4-triazolo [4,3-b] pyridazine (75 mg) was obtained as pale yellow crystals.
Example 18: 6- (6-azepan-1-yl-1,2,4-triazolo [4,3-b] pyridazin-3-yl) pyridin-2-ol (700 mg) and phosphorus tribromide (7 ml) )) Was stirred at 130 ° C. for 6 hours. The mixture was allowed to cool to room temperature, added with ice water, neutralized with a saturated aqueous solution of potassium carbonate, and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 98: 2), and recrystallized from ethanol to give 6-azepan-1-yl-3- (6-bromopyridine-2- Yl) -1,2,4-Triazolo [4,3-b] pyridazine (240 mg) as colorless crystals.
[0052]
Example 19: To a solution of diethyl {[(6-azepan-1-yl-1,2,4-triazolo [4,3-b] pyridazin-3-yl) methyl] phosphonate (367 mg) in THF (10 ml) was added ice. Under cooling, potassium tert-butoxide (127 mg) was added, and the mixture was stirred at room temperature for 40 minutes. 2-Bromobenzaldehyde (0.128 ml) was added to the obtained red solution, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting white solid was recrystallized from methanol to give 6-azepan-1-yl-3-[(E) -2- (2-bromophenyl) vinyl] -1,2,4-triazolo [4,3- b] Pyridazine (152 mg) was obtained as colorless crystals.
Example 20: A mixture of ethyl 6-chloro-1,2,4-triazolo [4,3-b] pyridazine-3-carboxylate (3.00 g) and hexamethyleneimine (10 ml) at 100 ° C. for 2 hours Stirred. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1), and the obtained crude crystals were recrystallized from ethanol and diethyl ether. And 3- (azepan-1-ylcarbonyl) -6-azepan-1-yl-1,2,4-triazolo [4,3-b] pyridazine (0.23 g) as colorless crystals.
[0053]
Example 21: {1- [3- (6-Methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] piperidin-6-yl] piperidin-3-ol (0.94 g) Pyridine (3 ml) and 4-toluenesulfonyl chloride (1.14 g) were added to a chloroform solution (12 ml) of, and the mixture was stirred at room temperature for 3 nights. Then, the reaction solution was subjected to silica gel column chromatography (eluent; chloroform: methanol = 30: 1) and purified by 1- [3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazin-6-yl] piperidin-3-yl @ 4-toluene Sulfonate (1.02 g) was obtained. This compound (0.34 g) was dissolved in DMSO (3 ml), sodium azide (0.14 g) was added, the mixture was stirred at 100 ° C. overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) to give 6- (3-azidopiperidin-1-yl) 1- [3- (6-methoxypyridine-2-yl). Yl) -1,2,4-triazolo [4,3-b] pyridazine (0.22 g). Dat (F: 352). Triphenylphosphine (0.20 g) was added to a THF solution (3 ml) of this compound (0.21 g), and the mixture was stirred at room temperature overnight. Water (1 ml) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 6 hours, cooled to room temperature, added with an aqueous sodium hydrogen carbonate solution, and extracted with a mixed solvent of chloroform and 2-propanol. The obtained organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent; chloroform: methanol: 29% aqueous ammonia = 30: 1: 0.1). Then, the residue is washed with diethyl ether-ethyl acetate to give 1- [3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazin-6-yl]. Piperidine-3-amine (90 mg) was obtained as a colorless amorphous substance.
Example 22: {1-[(benzyloxy) carbonyl] piperidine-3-carboxylic acid (2.44 g), 3-chloro-6-hydrazinopyridazine (1.34 g), WSCD hydrochloride (2.13 g) and chloride A mixture of methylene (60 ml) was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Acetic acid (80 ml) was added to the obtained residue, and the mixture was stirred at 110 ° C for 2 days, and then the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with ethanol and stirred in piperidine (10 ml) under heating and reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: chloroform: methanol = 97: 3). Ethanol (40 ml) and 10% palladium-carbon (150 mg) were added to the obtained colorless solid, and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours, and then the catalyst was removed by filtration. The obtained filtrate is concentrated under reduced pressure to give 6-piperidin-1-yl-3-piperidin-3-yl-1,2,4-triazolo [4,3-b] pyridazine (1.18 g) as colorless. Obtained as amorphous material.
[0054]
Example 23: A 1 M aqueous sodium hydroxide solution (30 ml) was added to a THF solution (200 ml) of {ethyl} 2-aminothiazole-4-carboxylate (4.56 g), and the mixture was stirred at room temperature for 3 hours. After adding 1 M hydrochloric acid (30 ml) to the reaction solution and concentrating, the obtained residue was dissolved in DMF (50 ml), and 6-chloropyridazin-3-ylhydrazine (3.83 g) and WSCD hydrochloride (6 ml) were added thereto. .09g) and stirred at room temperature. Water was added to the reaction solution, and the deposited precipitate was collected by filtration, washed with water and diethyl ether, acetic acid (30 ml) was added thereto, and the mixture was heated under reflux, and then concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Piperidine (10 ml) was added thereto, the mixture was heated at 100 ° C., the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1) to give 3 -(2'-Aminothiazol-4-yl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine (0.92 g) was obtained as a yellow solid.
Example 24: 6-Chloropicolinic acid (0.83 g) and WSCD hydrochloride (1.10 g) in a methylene chloride solution (10 ml) of 6-hydrazino-N-methyl-N-phenylpyridazin-3-amine (1.14 g). 22g) and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (eluent; chloroform), and 6-chloro-N ′-{6- [methyl (phenyl) amino] pyridazin-3-yl} pyridine-2-carbohydrazide (0.57 g) ) Got. This compound (0.56 g) was stirred in xylene (20 ml) at 150 ° C. overnight, and the reaction solution was concentrated to give 3- (6-chloropyridin-2-yl) -N-methyl-N-phenyl-1, 2,4-Triazolo [4,3-b] pyridazin-6-amine (0.54 g) was obtained as a colorless solid.
[0055]
Example 25: {6-chloro-3- (6-chloropyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (620 mg), heptamethyleneimine (1.32 g) and 1 , 4-Dioxane (20 ml) was stirred at 100 ° C. for 9 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed successively with a 5% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethanol, and 6-azocan-1-yl-3- (6-chloropyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine (370 mg) ) Was obtained as off-white crystals.
Example 26: A mixture of {6- (6-chloro-1,2,4-triazolo [4,3-b] pyridazin-3-yl) pyridin-2-ol (960 mg) and piperidine (10 ml) at 100 ° C. Stir for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained crystalline residue was recrystallized from ethanol to give 6- (6-piperidin-1-yl-1,2,4-triazolo [4 [3-B] pyridazin-3-yl) pyridin-2-ol (820 mg) was obtained as off-white crystals.
[0056]
Example 27: To a solution of 6-amino-3- (3-methoxyphenyl) -1,2,4-triazolo [4,3-a] pyridine (410 mg) in THF (5 ml) at -5 to 0C was added 50. % Glutaraldehyde aqueous solution (0.33 ml), water (0.33 ml), a mixture of 3M sulfuric acid 2.2 ml, methanol (3.8 ml), THF (2.5 ml), and sodium borohydride (150 mg) were added. Stir for 2 hours. A 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 1). After the obtained residue was dissolved in ethyl acetate, a 4M hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from acetonitrile to give 3- (3-methoxyphenyl) -6-piperidin-1-yl-1,2,4-triazolo [4,3-a]. Pyridine dihydrochloride (21 mg) was obtained as a brown solid.
Example 28: DMF of 6-azepan-1-yl-3-[(E) -2- (2-methoxyphenyl) vinyl] -1,2,4-triazolo [4,3-b] pyridazine (830 mg) After adding 10% palladium-carbon (800 mg) to the (25 ml) solution, the mixture was stirred at room temperature under a hydrogen gas (1 atm) atmosphere for 40 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1), 4M hydrogen chloride-ethyl acetate (1 ml) is added, and the deposited precipitate is washed with ethyl acetate, and washed with ethyl acetate. Azepan-1-yl-3- [2- (2-methoxyphenyl) ethyl] -7,8-dihydro-1,2,4-triazolo [4,3-b] pyridazine hydrochloride (74 mg) as colorless crystals. As obtained.
[0057]
The same treatment as in Example 1 was performed, and if necessary, the mixture was subjected to a conventional salt formation reaction using 4M hydrogen chloride-ethyl acetate. The results are shown in Examples 29 to 169 and Table 20 shown in Tables 7 to 17 below. The compounds of Examples 201 to 209 were obtained. Further, the compound of Example 170 shown in Table 17 in the same manner as in Example 2, the compound of Example 171 in the same manner as in Example 3, and the compound of Examples 172 and 173 in the same manner as in Example 4 In the same manner as in Example 5, the compounds of Examples 174 and 175, in the same manner as in Example 6, the compounds of Example 176, and in the same manner as in Example 9, the compounds of Examples 177 to 179 shown in Table 18. The compounds of Examples 180 and 181 in the same manner as in Example 13, the compounds of Example 182 in the same manner as in Example 16, and the compounds of Examples 183 to 185 in the same manner as in Example 18 were prepared. The compounds of Examples 186 to 197 shown in Tables 18 to 19 in the same manner as in Example 19, the compounds of Example 198 shown in Table 19 in the same manner as in Example 25, and the Examples in the same manner as in Example 26 199-2 0 compound was obtained, respectively.
[0058]
Tables 1 to 5 below show the structural formulas and physicochemical properties of the reference example compounds, and Tables 6 to 20 show the structural formulas and physicochemical properties of the example compounds. Also, in Table 21, each No. R shown in 1 to 20¹Compounds of the formulas (I-1) to (I-4) having a group can be prepared by using the appropriate starting compounds in substantially the same manner as in the methods described in the above Examples or Production Methods, or by applying them. It is easily manufactured, applying some obvious modifications to the trader.
The abbreviations in the table are Rex: reference example number; {Ex: example number; {Str: structural formula;⁺ΔM: melting point [° C.]; Δ (d): decomposition; ΔN1: NMR (DMSO-d₆, TMS internal standard); Sal: salt (blank: free form; HCl: hydrochloride; 2HCl: dihydrochloride); メ チ ル Me: methyl; Et: ethyl; and Ac: acetyl, respectively.
[0059]
[Table 1]

[0060]
[Table 2]

[0061]
[Table 3]

[0062]
[Table 4]

[0063]
[Table 5]

[0064]
[Table 6]

[0065]
[Table 7]

[0066]
[Table 8]

[0067]
[Table 9]

[0068]
[Table 10]

[0069]
[Table 11]

[0070]
[Table 12]

[0071]
[Table 13]

[0072]
[Table 14]

[0073]
[Table 15]

[0074]
[Table 16]

[0075]
[Table 17]

[0076]
[Table 18]

[0077]
[Table 19]

[0078]
[Table 20]

[0079]
[Table 21]

[Brief description of the drawings]
FIG. 1 shows the osteoid width of a group administered with the compound of the present invention and a control group in Test Example 2.
FIG. 2 shows the calcification rates of the compound of the present invention and the control group in Test Example 2.

Claims (4)

A nitrogen-containing heterocyclic compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.
X ¹ and X ² : same or different, N or CR ⁵ , provided that at least one is N,
Y: N, or when X ¹ and X ² are both N, Y may be CR ⁶ ;
Dotted line: single bond or double bond,
R ¹ : —NRaRb, provided that when the group —ER ² is phenyl having a substituent at the m-position or 2-pyridyl having a substituent at the 6-position, R ¹ may have a substituent Good aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, -O- (optionally substituted aryl), -S- (substituent aryl which may have), - O-C _1-2 alkylene - (aryl which may have a substituent), - O-C _1-2 alkylene - (which may have a substituent A 4- to 8-membered monocyclic saturated or partially unsaturated heterocyclic ring) or —OC _1-2 alkylene-OR ′.
Ra and Rb: identical or different, H; CO-lower alkyl; SO ₂ -lower alkyl; cycloalkyl optionally having substituent (s); aryl optionally having substituent (s); Optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, CO-lower alkyl, SO ₂ -lower alkyl, OR ′, SR ′, NR′R ″, halogen, NO ₂ , CN, and lower alkyl optionally having 1 to 3 substituents selected from the group consisting of COOR ′ Provided that at least one of Ra and Rb represents a group other than H;
Alternatively, Ra and Rb are combined with an adjacent N atom to form a 4- to 8-membered saturated or unsaturated heterocycle containing 1 to 2 N atoms as a heteroatom, and the heterocycle is a benzene ring or May be condensed with a cycloalkyl ring, may have a bridge or may form a spiro ring, furthermore, the hetero ring may have 1 to 5 substituents,
E: single bond, C _1-3 alkylene, vinylene (—C ＝ C—), ethynylene (—C≡C—), CO, NR ⁷ , CH ₂ —J, CONR ⁸ or NR ⁹ CO;
J: O, S, NR ¹⁰ , CO, SO or SO ₂ ,
R ² : aryl which may have a substituent, heteroaryl which may have a substituent, cycloalkyl which may have a substituent, cycloalkenyl which may have a substituent, An optionally substituted 4- to 8-membered monocyclic saturated or partially unsaturated heterocycle, -OR 'or -P (= O) (OR') ₂
R ^{3 to} R ¹⁰ , R ′ and R ″: identical or different, H or lower alkyl, except for the following compounds.
(1) X ¹ , X ² and Y are N, Ra and Rb are united with an adjacent N atom to form piperidino, R ³ and R ⁴ are both H, E is a single bond, and R ² is piperidino. A compound which is unsubstituted phenyl, p- (trifluoromethyl) phenyl, p-chlorophenyl or o-nitrophenyl;
(2) X ¹ , X ² and Y are N, Ra and Rb are united with an adjacent N atom to form piperidino, R ³ is H, R ⁴ is methyl, E is a single bond, and R ² is A compound which is unsubstituted phenyl, m-methylphenyl, p-chlorophenyl, m-methoxyphenyl or p-nitrophenyl;
(3) X ¹ , X ² and Y are N, Ra and Rb are combined with an adjacent N atom to form 4-methyl-1-piperazinyl, E is a single bond, and R ² is unsubstituted phenyl A compound which is, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, m-chlorophenyl, p-chlorophenyl or m-nitrophenyl;
(4) a compound wherein X ¹ , X ² and Y are N, and R ² is imidazolyl, 5-nitro-2-furyl or 5-nitro-2-thienyl which may have a substituent,
(5) X ¹ , X ² and Y are N, and Ra and Rb are integrated with an adjacent N atom to form 1-pyrazolyl which may have a substituent, E is a single bond, and R ^A compound wherein ² is unsubstituted phenyl or morpholino,
(6) a compound in which X ¹ , X ² and Y are N, Ra is H, Rb is cyclopropyl, E is a single bond, and R ² is p- (trifluoromethyl) phenyl, and (7) X ¹ , A compound wherein X ² and Y are N, Ra is methyl, Rb is 2-hydroxy-propyl, E is a single bond, and R ² is 3-pyridyl. ) 6-azocan-1-yl-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azepan-1-yl-3- (6- Bromopyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 3- (3-methoxyphenyl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine, 3- (3-bromophenyl) -6- (piperidin-1-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azepan-1- Yl-3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6- (4-fluoropiperidin-1-yl) -3- (6-methoxy) Pyridin-2-yl) -1,2,4-triazolo [4,3-b] Ridazine, 6- (3-azabicyclo [3.2.1] octan-3-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine , 6- (4,4-difluoropiperidin-1-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6- (3 3-difluoropiperidin-1-yl) -3- (6-methoxypyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine, 6-azocan-1-yl-3- ( 6-bromopyridin-2-yl) -1,2,4-triazolo [4,3-b] pyridazine and 6- (8-azabicyclo [3.2.1] octan-8-yl) -3- ( 6-bromopyridin-2-yl) -1,2,4-triazolo [4 3-b] nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein is selected from pyridazine. A medicament comprising the nitrogen-containing heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The medicament according to claim 3, which is an osteogenesis promoter.

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